Solid forms comprising 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione and a coformer, compositions and methods of use thereof

ABSTRACT

Provided herein are solid forms comprising (a) 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione and (b) a coformer. Pharmaceutical compositions comprising the solid forms (e.g., cocrystals) and methods for treating, preventing and managing various disorders are also disclosed.

This application is a Divisional of U.S. application No. 14/780,289,filed Sep. 25, 2015, which is a national phase entry pursuant to 35U.S.C. § 371 of International Application No. PCT/US2014/031694, filedMar. 25, 2014, which claims priority to U.S. Provisional Application No.61/805,444, filed Mar. 26, 2013, the entirety of each of which isincorporated herein by reference.

1. FIELD

Provided herein are solid forms comprising4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione and acoformer. Pharmaceutical compositions comprising such solid forms (e.g.,cocrystals) and methods of use for treating, preventing, and managingvarious disorders are also provided herein.

2. BACKGROUND

2.1 Solid Forms of Pharmaceutical Compounds

The identification and selection of a solid form of a pharmaceuticalcompound are complex, given that a change in solid form may affect avariety of physical and chemical properties, which may provide benefitsor drawbacks in processing, formulation, stability, bioavailability,storage, handling (e.g., shipping), among other important pharmaceuticalcharacteristics. Useful pharmaceutical solids include crystalline solidsand amorphous solids, depending on the product and its mode ofadministration. Amorphous solids are characterized by a lack oflong-range structural order, whereas crystalline solids arecharacterized by structural periodicity. The desired class ofpharmaceutical solid depends upon the specific application; amorphoussolids are sometimes selected on the basis of, e.g., an enhanceddissolution profile, while crystalline solids may be desirable forproperties such as, e.g., physical or chemical stability (see, e.g., S.R. Vippagunta et al., Adv. Drug. Deliv. Rev., (2001) 48:3-26; L. Yu,Adv. Drug. Deliv. Rev., (2001) 48:27-42).

Whether crystalline or amorphous, solid forms of a pharmaceuticalcompound include single-component and multiple-component solids.Single-component solids consist essentially of the pharmaceuticalcompound or active ingredient in the absence of other compounds. Varietyamong single-component crystalline materials may potentially arise fromthe phenomenon of polymorphism, wherein multiple three-dimensionalarrangements exist for a particular pharmaceutical compound (see, e.g.,S. R. Byrn et al., Solid State Chemistry of Drugs, (1999) SSCI, WestLafayette). The importance of discovering polymorphs was underscored bythe case of Ritonavir™, an HIV protease inhibitor that was formulated assoft gelatin capsules. About two years after the product was launched,the unanticipated precipitation of a new, less soluble polymorph in theformulation necessitated the withdrawal of the product from the marketuntil a more consistent formulation could be developed (see S. R.Chemburkar et al., Org. Process Res. Dev., (2000) 4:413-417).

Additional diversity among the potential solid forms of a pharmaceuticalcompound may arise from the possibility of multiple-component solids.Crystalline solids comprising two or more ionic species may be termedsalts (see, e.g., Handbook of Pharmaceutical Salts: Properties,Selection and Use, P. H. Stahl and C. G. Wermuth, Eds., (2002), Wiley,Weinheim). Additional types of multiple-component solids that maypotentially offer other property improvements for a pharmaceuticalcompound or salt thereof include, e.g., hydrates, solvates, co-crystalsand clathrates, among others (see, e.g., S. R. Byrn et al., Solid StateChemistry of Drugs, (1999) SSCI, West Lafayette). Moreover,multiple-component crystal forms may potentially be susceptible topolymorphism, wherein a given multiple-component composition may existin more than one three-dimensional crystalline arrangement.

Cocrystals are crystalline molecular complexes of two or morenon-volatile compounds bound together in a crystal lattice by non-ionicinteractions. Pharmaceutical cocrystals are cocrystals of a therapeuticcompound, e.g., an active pharmaceutical ingredient (API), and one ormore non-volatile compound(s) (referred to herein as coformer). Acoformer in a pharmaceutical cocrystal is typically a non-toxicpharmaceutically acceptable molecule, such as, for example, foodadditives, preservatives, pharmaceutical excipients, or other APIs. Inrecent years, pharmaceutical cocrystals have emerged as a possiblealternative approach to enhance physicochemical properties of drugproducts.

The variety of possible solid forms creates potential diversity inphysical and chemical properties for a given pharmaceutical compound.The discovery and selection of solid forms are of great importance inthe development of an effective, stable and marketable pharmaceuticalproduct.

2.2 Pomalidomide

Pomalidomide, which was previously referred to as CC-4047, and has achemical name of4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione. Pomalidomideis a compound that inhibits, for example, LPS induced monocyte TNFα,IL-1β, IL-12, IL-6, MIP-1, MCP-1, GM-CSF, G-CSF, and COX-2 production,and may be used in treating various disorders. See, e.g., U.S. Pat. Nos.5,635,517, 6,316,471, 6,476,052, 7,393,863, 7,629,360, and 7,863,297;and U.S. Patent Application Publication Nos. 2005/0143420, 2006/0166932,2006/0188475, 2007/0048327, 2007/0066512, 2007/0155791, 2008/0051431,2008/0317708, 2009/0087407, 2009/0088410, 2009/01317385, 2009/0148853,2009/0232776, 2009/0232796, 2010/0098657, 2010/0099711, and2011/0184025, the entireties of which are incorporated herein byreference. The compound is also known to co-stimulate the activation ofT-cells. Pomalidomide has direct anti-myeloma tumoricidal activity,immunomodulatory activities and inhibits stromal cell support formultiple myeloma tumor cell growth. Specifically, pomalidomide inhibitsproliferation and induces apoptosis of hematopoietic tumor cells. Id.Additionally, pomalidomide inhibits the proliferation oflenalidomide-resistant multiple myeloma cell lines and synergizes withdexamethasone in both lenalidomide-sensitive and lenalidomide-resistantcell lines to induce tumor cell apoptosis. Pomalidomide enhances T cell-and natural killer (NK) cell-mediated immunity, and inhibits productionof pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes.Pomalidomide also inhibits angiogenesis by blocking the migration andadhesion of endothelial cells. Due to its diversified pharmacologicalproperties, pomalidomide is useful in treating, preventing, and/ormanaging various diseases or disorders.

Pomalidomide and methods of synthesizing the compound are described,e.g., in U.S. Pat. Nos. 5,635,517, 6,335,349, 6,316,471, 6,476,052,7,041,680, 7,709,502, and 7,994,327; and U.S. Patent ApplicationPublication Nos. 2006/0178402 and 2011/0224440; the entireties of whichare incorporated herein by reference.

Citation of any references in this Section is not to be construed as anadmission that such references are prior art to the present application.

3. SUMMARY

Provided herein are solid forms (e.g., crystal forms or amorphous forms,or mixtures thereof) comprising pomalidomide, or pharmaceuticallyacceptable salts, stereoisomers, solvates (including, hydrates),prodrugs, or clathrates thereof, and a coformer. Also provided aremethods of preparing, isolating, and characterizing the solid forms.

Also provided herein are pharmaceutical compositions and single unitdosage forms, which comprise one or more solid forms provided herein.

Also provided herein are methods of treating and managing variousdiseases or disorders. The methods comprise administering to a patientin need of such treatment or management a therapeutically effectiveamount of a solid form provided herein.

Also provided herein are methods of preventing various diseases anddisorders, which comprise administering to a patient in need of suchprevention a prophylactically effective amount of a solid form providedherein.

The various diseases and disorders include, but are not limited to:cancer, including hematologic cancer or solid tumor, for example,multiple myeloma, leukemia, lymphoma, sarcoma, prostate cancer, or smallcell lung cancer; scleroderma; amyloidosis; pain; myelofibrosis;myeloproliferative disease, for example, myelofibrosis with myeloidmetaplasia (MMM); myelodysplastic syndromes; diffuse systemic sclerosis;macular degeneration; a skin disease; a pulmonary disorder, anasbestos-related disorder; a parasitic disease; an immunodeficiencydisorder; a CNS disorder, a CNS injury; atherosclerosis;hemoglobinopathy; anemia, for example, sickle cell anemia; aninflammatory disease; an autoimmune disease; a viral disease; a geneticdisease; an allergic disease; a bacterial disease; an ocular neovasculardisease; a choroidal neovascular disease; a retina neovascular disease;and rubeosis.

4. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a representative X-ray Powder Diffraction (XRPD) patternof one embodiment of a solid form comprising pomalidomide and gallicacid.

FIG. 2 provides a representative XRPD pattern of one embodiment of asolid form comprising pomalidomide and vanillin.

FIG. 3 provides a representative XRPD pattern of one embodiment of asolid form comprising pomalidomide and cyclamic acid.

FIG. 4 provides a representative XRPD pattern of one embodiment of asolid form comprising pomalidomide and D-glucose.

FIG. 5 provides a representative XRPD pattern of one embodiment of asolid form comprising pomalidomide and propyl gallate.

FIG. 6 provides a representative XRPD pattern of one embodiment of asolid form comprising pomalidomide and saccharin.

FIG. 7 provides a representative XRPD pattern of one embodiment of asolid form comprising pomalidomide and sodium lauryl sulfate.

FIG. 8 provides a representative XRPD pattern of one embodiment of asolid form comprising pomalidomide and magnesium bromide.

FIG. 9 provides a representative XRPD pattern of one embodiment of asolid form comprising pomalidomide and malonic acid.

FIG. 10 provides a representative XRPD pattern of one embodiment of asolid form comprising pomalidomide and maltol.

FIG. 11 provides a representative XRPD pattern of one embodiment of asolid form comprising pomalidomide and methyl paraben.

FIG. 12 provides a representative XRPD pattern of one embodiment of asolid form comprising pomalidomide and zinc chloride.

FIG. 13A provides a representative XRPD pattern of one embodiment of asolid form comprising Form A of pomalidomide.

FIG. 13B provides a representative XRPD pattern of one embodiment of asolid form comprising Form B of pomalidomide.

FIG. 14 provides a representative thermal gravimetric analysis (TGA)thermogram and a representative differential scanning calorimetry (DSC)thermogram of a solid form comprising Form B of pomalidomide.

5. DETAILED DESCRIPTION

5.1 Definitions

As used herein, and in the specification and the accompanying claims,the indefinite articles “a” and “an” and the definite article “the”include plural as well as single referents, unless the context clearlyindicates otherwise.

As used herein, and unless otherwise specified, the compound referred toherein by the name pomalidomide,4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione, or CC-4047,corresponds to chemical structure (I), depicted below. In certainembodiments, the term pomalidomide,4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione, or CC-4047may be used herein to refer to either a free base form or an ionizedform of a compound of formula (I) (e.g., the molecule is protonated atone or more basic centers).

Unless otherwise specified, the terms “solid form,” “solid forms,” andrelated terms, when used herein to refer to pomalidomide, refer to aphysical form comprising pomalidomide, which is not predominantly in aliquid or a gaseous state. As used herein, the terms “solid form” and“solid forms” encompass semi-solids. Solid forms may be crystalline,amorphous, partially crystalline, partially amorphous, or mixtures offorms. A “single-component” solid form comprising pomalidomide consistsessentially of pomalidomide. A “multiple-component” solid formcomprising pomalidomide comprises a significant quantity of one or moreadditional species, such as ions and/or molecules, within the solidform. For example, in particular embodiments, a crystallinemultiple-component solid form comprising pomalidomide further comprisesone or more species non-covalently bonded at regular positions in thecrystal lattice.

Unless otherwise specified, the term “crystalline” and related termsused herein, when used to describe a substance, component, product, orform, mean that the substance, component, product, or form issubstantially crystalline, for example, as determined by X-raydiffraction. (see, e.g., Remington's Pharmaceutical Sciences, 18^(th)ed., Mack Publishing, Easton Pa., 173 (1990); The United StatesPharmacopeia, 23^(rd) ed., 1843-1844 (1995)).

Unless otherwise specified, the term “crystal form,” “crystal forms,”and related terms herein refer to crystalline modifications comprising agiven substance, including single-component crystal forms andmultiple-component crystal forms, and including, but not limited to,polymorphs, solvates, hydrates, co-crystals, other molecular complexes,salts, solvates of salts, hydrates of salts, co-crystals of salts, andother molecular complexes of salts, and polymorphs thereof. In someembodiments, a crystal form of a substance may be substantially free ofamorphous forms and/or other crystal forms. In other embodiments, acrystal form of a substance may contain less than about 1%, 2%, 3%, 4%,5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% of one or moreamorphous form(s) and/or other crystal form(s) on a weight basis.Crystal forms of a substance may be obtained by a number of methods.Such methods include, but are not limited to, melt recrystallization,melt cooling, solvent recrystallization, recrystallization in confinedspaces such as, e.g., in nanopores or capillaries, recrystallization onsurfaces or templates such as, e.g., on polymers, recrystallization inthe presence of additives, such as, e.g., co-crystal counter-molecules,desolvation, dehydration, rapid evaporation, rapid cooling, slowcooling, vapor diffusion, sublimation, grinding, and solvent-dropgrinding.

Unless otherwise specified, the terms “polymorph,” “polymorphic form,”“polymorphs,” “polymorphic forms,” and related terms herein refer to twoor more crystal forms that consist essentially of the same molecule,molecules or ions. Different polymorphs may have different physicalproperties, such as, for example, melting temperatures, heats of fusion,solubilities, dissolution rates, and/or vibrational spectra as a resultof a different arrangement or conformation of the molecules or ions inthe crystal lattice. The differences in physical properties exhibited bypolymorphs may affect pharmaceutical parameters, such as storagestability, compressibility and density (important in formulation andproduct manufacturing), and dissolution rate (an important factor inbioavailability). Differences in stability can result from changes inchemical reactivity (e.g., differential oxidation, such that a dosageform discolors more rapidly when comprised of one polymorph than whencomprised of another polymorph) or mechanical changes (e.g., tabletscrumble on storage as a kinetically favored polymorph converts tothermodynamically a more stable polymorph) or both (e.g., tablets of onepolymorph are more susceptible to breakdown at high humidity). As aresult of solubility/dissolution differences, in the extreme case, somepolymorphic transitions may result in lack of potency or, at the otherextreme, toxicity. In addition, the physical properties of the crystalmay be important in processing; for example, one polymorph might be morelikely to form solvates or might be difficult to filter and wash free ofimpurities (e.g., particle shape and size distribution might bedifferent between polymorphs).

Unless otherwise specified, the term “cocrystal” or “co-crystal,” asused herein, refers to a crystalline material comprised of two or morenon-volative compounds bond together in a crystal lattice bynon-covalent interactions.

Unless otherwise specified, the term “pharmaceutical cocrystal” or“cocrystal” of an active pharmaceutical ingredient (API), as usedherein, refers to a crystalline material comprised of an API and one ormore non-volative compound(s) (referred herein as a coformer). The APIand the coformer interact through non-covalent forces in a crystallattice.

Unless otherwise specified, the term “amorphous,” “amorphous form,” andrelated terms used herein mean that the substance, component, or productreferred to is not substantially crystalline as determined by X-raydiffraction. In certain embodiments, an amorphous form of a substancemay be substantially free of crystal forms. In other embodiments, anamorphous form of a substance may contain less than about 1%, 2%, 3%,4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or morecrystal forms on a weight basis. In other embodiments, an amorphous formof a substance may comprise additional components or ingredients (forexample, an additive, a polymer, or an excipient that may serve tofurther stabilize the amorphous form). In some embodiments, amorphousform may be a solid solution. Amorphous forms of a substance can beobtained by a number of methods. Such methods include, but are notlimited to, heating, melt cooling, rapid melt cooling, solventevaporation, rapid solvent evaporation, desolvation, sublimation,grinding, ball-milling, cryo-grinding, spray drying, and freeze drying.

As used herein, and unless otherwise specified, the terms “about” and“approximately,” when used in connection with doses, amounts, or weightpercents of ingredients of a composition or a dosage form, mean a dose,amount, or weight percent that is recognized by one of ordinary skill inthe art to provide a pharmacological effect equivalent to that obtainedfrom the specified dose, amount, or weight percent. In certainembodiments, the terms “about” and “approximately,” when used in thiscontext, contemplate a dose, amount, or weight percent within 30%,within 20%, within 15%, within 10%, or within 5%, of the specified dose,amount, or weight percent.

As used herein, and unless otherwise specified, the terms “about” and“approximately,” when used in connection with a numeric value or rangeof values which is provided to characterize a particular solid form,e.g., a specific temperature or temperature range, such as, for example,that describes a melting, dehydration, desolvation, or glass transitiontemperature; a mass change, such as, for example, a mass change as afunction of temperature or humidity; a solvent or water content, interms of, for example, mass or a percentage; or a peak position, suchas, for example, in analysis by, for example, IR or Raman spectroscopyor XRPD; indicate that the value or range of values may deviate to anextent deemed reasonable to one of ordinary skill in the art while stilldescribing the solid form. Techniques for characterizing crystal formsand amorphous forms include, but are not limited to, thermal gravimetricanalysis (TGA), differential scanning calorimetry (DSC), X-ray powderdiffractometry (XRPD), single-crystal X-ray diffractometry, vibrationalspectroscopy, e.g., infrared (IR) and Raman spectroscopy, solid-stateand solution nuclear magnetic resonance (NMR) spectroscopy, opticalmicroscopy, hot stage optical microscopy, scanning electron microscopy(SEM), electron crystallography and quantitative analysis, particle sizeanalysis (PSA), surface area analysis, solubility studies, anddissolution studies. In certain embodiments, the terms “about” and“approximately,” when used in this context, indicate that the numericvalue or range of values may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%,6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value orrange of values. For example, in some embodiments, the value of an XRPDpeak position may vary by up to ±0.2 degrees two theta while stilldescribing the particular XRPD peak.

As used herein, and unless otherwise specified, a crystalline oramorphous form that is “pure,” i.e., substantially free of othercrystalline or amorphous forms, contains less than about 10% by weightof one or more other crystalline or amorphous forms, less than about 5%by weight of one or more other crystalline or amorphous forms, less thanabout 3% by weight of one or more other crystalline or amorphous forms,or less than about 1% by weight of one or more other crystalline oramorphous forms.

As used herein, and unless otherwise specified, a solid form that is“substantially physically pure” is substantially free from other solidforms. In certain embodiments, a crystal form that is substantiallyphysically pure contains less than about 50%, 45%, 40%, 35%, 30%, 25%,20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%,0.2%, 0.1%, 0.05%, or 0.01% of one or more other solid forms on a weightbasis. The detection of other solid forms can be accomplished by anymethod apparent to a person of ordinary skill in the art, including, butnot limited to, diffraction analysis, thermal analysis, elementalcombustion analysis and/or spectroscopic analysis.

As used herein, and unless otherwise specified, a solid form that is“substantially chemically pure” is substantially free from otherchemical compounds (i.e., chemical impurities). In certain embodiments,a solid form that is substantially chemically pure contains less thanabout 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% of one ormore other chemical compounds on a weight basis. The detection of otherchemical compounds can be accomplished by any method apparent to aperson of ordinary skill in the art, including, but not limited to,methods of chemical analysis, such as, e.g., mass spectrometry analysis,spectroscopic analysis, thermal analysis, elemental combustion analysisand/or chromatographic analysis.

As used herein, and unless otherwise indicated, a chemical compound,solid form, or composition that is “substantially free” of anotherchemical compound, solid form, or composition means that the compound,solid form, or composition contains, in certain embodiments, less thanabout 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2% 0.1%, 0.05%, or 0.01% by weightof the other compound, solid form, or composition.

As used herein, and unless otherwise specified, the term“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable, relatively non-toxic acids, includinginorganic acids and organic acids. In some embodiments, suitable acidsinclude, but are not limited to, acetic, benzenesulfonic, benzoic,camphorsulfonic, carbonic, citric, dihydrogenphosphoric, ethenesulfonic,fumaric, galactunoric, gluconic, glucuronic, glutamic, hydrobromic,hydrochloric, hydriodic, isobutyric, isethionic, lactic, maleic, malic,malonic, mandelic, methanesulfonic, monohydrogencarbonic,monohydrogen-phosphoric, monohydrogensulfuric, mucic, nitric, pamoic,pantothenic, phosphoric, phthalic, propionic, suberic, succinic,sulfuric, tartaric, toluenesulfonic acid (including p-toluenesulfonic,m-toluenesulfonic, and o-toluenesulfonic acids), and the like (see,e.g., S. M. Berge et al., J. Pharm. Sci., 66:1-19 (1977); and Handbookof Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl andC. G. Wermuth, Eds., (2002), Wiley, Weinheim). In some embodiments,suitable acids are strong acids (e.g., with pKa less than about 1),including, but not limited to, hydrochloric, hydrobromic, sulfuric,nitric, methanesulfonic, benzene sulfonic, toluene sulfonic, naphthalenesulfonic, naphthalene disulfonic, pyridine-sulfonic, or othersubstituted sulfonic acids. Also included are salts of other relativelynon-toxic compounds that possess acidic character, including aminoacids, such as aspartic acid and the like, and other compounds, such asaspirin, ibuprofen, saccharin, and the like. Acid addition salts can beobtained by contacting the neutral form of a compound with a sufficientamount of the desired acid, either neat or in a suitable solvent. Assolids, salts can exist in crystalline or amorphous forms, or mixturesthereof. Salts can also exist in polymorphic forms.

Unless otherwise specified, the terms “solvate” and “solvated,” as usedherein, refer to a solid form of a substance which contains solvent. Theterms “hydrate” and “hydrated” refer to a solvate wherein the solvent iswater. “Polymorphs of solvates” refer to the existence of more than onesolid form for a particular solvate composition. Similarly, “polymorphsof hydrates” refer to the existence of more than one solid form for aparticular hydrate composition. The term “desolvated solvate,” as usedherein, refers to a solid form of a substance which can be made byremoving the solvent from a solvate. The terms “solvate” and “solvated,”as used herein, can also refer to a solvate of a salt, co-crystal, ormolecular complex. The terms “hydrate” and “hydrated,” as used herein,can also refer to a hydrate of a salt, co-crystal, or molecular complex.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” refer to the eradication or amelioration of adisease or disorder, or of one or more symptoms associated with thedisease or disorder. In certain embodiments, the terms refer tominimizing the spread or worsening of the disease or disorder resultingfrom the administration of one or more prophylactic or therapeuticagents to a subject with such a disease or disorder. In someembodiments, the terms refer to the administration of a compoundprovided herein, with or without other additional active agent, afterthe onset of symptoms of a particular disease.

As used herein, and unless otherwise specified, the terms “prevent,”“preventing” and “prevention” refer to the prevention of the onset,recurrence or spread of a disease or disorder, or of one or moresymptoms thereof. In certain embodiments, the terms refer to thetreatment with or administration of a compound provided herein, with orwithout other additional active compound, prior to the onset ofsymptoms, particularly to patients at risk of a disease or disorderprovided herein. The terms encompass the inhibition or reduction of asymptom of a particular disease. Patients with familial history of adisease in particular are candidates for preventive regimens in certainembodiments. In addition, patients who have a history of recurringsymptoms are also potential candidates for the prevention. In thisregard, the term “prevention” may be interchangeably used with the term“prophylactic treatment.”

As used herein, and unless otherwise specified, the terms “manage,”“managing” and “management” refer to preventing or slowing theprogression, spread, or worsening of a disease or disorder, or of one ormore symptoms thereof. Often, the beneficial effects that a subjectderives from a prophylactic and/or therapeutic agent do not result in acure of the disease or disorder. In this regard, the term “managing”encompasses treating a patient who had suffered from the particulardisease in an attempt to prevent or minimize the recurrence of thedisease or one or more symptoms thereof.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of a disease ordisorder, or to delay or minimize one or more symptoms associated withthe disease or disorder. A therapeutically effective amount of acompound means an amount of therapeutic agent, alone or in combinationwith other therapies, that provides a therapeutic benefit in thetreatment or management of the disease or disorder. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease ordisorder, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease or disorder, or one or more symptoms thereof, or prevent therecurrence of the disease or disorder, or one or more symptoms thereof.A prophylactically effective amount of a compound means an amount oftherapeutic agent, alone or in combination with other agents, thatprovides a prophylactic benefit in the prevention of the disease ordisorder. The term “prophylactically effective amount” can encompass anamount that improves overall prophylaxis or enhances the prophylacticefficacy of another prophylactic agent.

Unless otherwise specified, the term “composition” as used herein isintended to encompass a product comprising the specified ingredient(s)(and in the specified amount(s), if indicated), as well as any productwhich results, directly or indirectly, from combination of the specifiedingredient(s) in the specified amount(s). By “pharmaceuticallyacceptable,” it is meant a diluent, excipient, or carrier in aformulation must be compatible with the other ingredient(s) of theformulation and not deleterious to the recipient thereof.

Unless otherwise specified, the term “therapeutically andprophylactically effective amount” refers to the amount of the subjectsolid form that will elicit the biological or medical response of atissue, system, animal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician or that is sufficient toprevent development of or alleviate to some extent one or more of thesymptoms of the disease being treated.

Unless otherwise specified, the term “subject” is defined herein toinclude animals, such as mammals, including, but not limited to,primates (e.g., humans), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice, and the like. In specific embodiments, the subjectis a human.

Unless otherwise specified, to the extent that there is a discrepancybetween a depicted chemical structure of a compound provided herein anda chemical name of a compound provided herein, the chemical structureshall control.

5.2 Solid Forms Comprising Pomalidomide and a Coformer

In one embodiment, provided herein are solid forms (e.g., crystal forms,amorphous forms, or mixtures thereof) comprising (a) pomalidomide, or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,prodrug, or clathrate thereof; and (b) a coformer. In one embodiment,provided herein are solid forms (e.g., crystal forms, amorphous forms,or mixtures thereof) comprising (a) a free base of pomalidomide, or asolvate, hydrate, stereoisomer, prodrug, or clathrate thereof; and (b) acoformer. Pomalidomide can be synthesized or obtained according to amethod known in the literature or based upon the teachings herein,including the methods described in detail in the examples herein.

In one embodiment, pomalidomide can be prepared according to methodsdescribed in, for example, U.S. Pat. Nos. 5,635,517, 6,335,349,6,316,471, 6,476,052, 7,041,680, 7,709,502, and 7,994,327; and U.S.Patent Application Publication Nos. 2006/0178402 and 2011/0224440; theentireties of which are incorporated herein by reference.

The coformer can be any pharmaceutically acceptable coformer known inthe art. In one embodiment, the coformer is acetylsalicylic acid,D-glucose, nicotinic acid, aconitic acid, L-glutamic acid, oxalic acid,adipic acid, glutaric acid, L-proline, 4-aminosalicylic acid, glycine,propyl gallate, L-ascorbic acid, glycolic acid, L-pyroglutamic acid,benzoic acid, hippuric acid, saccharin, (+)-camphoric acid,1-hydroxy-2-naphthoic acid, salicylic acid, capric acid, ketoglutaricacid, sebacic acid, cinnamic acid, L-lysine, sodium lauryl sulfate,citric acid, magnesium bromide, sorbic acid, cyclamic acid, maleic acid,succinic acid, ethyl maltol, L-malic acid, L-tartaric acid, ethylparaben, malonic acid, urea, D-fructose, maltol, vanillic acid, fumaricacid, D,L-mandelic acid, vanillin, gallic acid, methyl paraben, zincchloride, gentisic acid, or nicotinamide.

In one embodiment, the coformer is gallic acid, vanillin, cyclamic acid,D-glucose, magnesium bromide, malonic acid, maltol, methyl paraben,propyl gallate, saccharin, sodium lauryl sulfate, or zinc chloride.

In one embodiment, solid forms provided herein may be a crystal form oran amorphous form or mixtures thereof (e.g., mixtures of crystal forms,or mixtures of crystal and amorphous forms), which comprises (a)pomalidomide or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, prodrug, or clathrate thereof; and (b) a coformer. In oneembodiment, provided herein is a crystal form comprising (a)pomalidomide or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, prodrug, or clathrate thereof; and (b) a coformer. In oneembodiment, provided herein is a cocrystal comprising (a) pomalidomideor a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,prodrug, or clathrate thereof; and (b) a coformer. In one embodiment,provided herein is an amorphous form comprising (a) pomalidomide or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,prodrug, or clathrate thereof; and (b) a coformer. In one embodiment,provided herein is a mixture comprising (i) a cocrystal comprising (a)pomalidomide or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, prodrug, or clathrate thereof; and (b) a coformer; and(ii) a crystal form of pomalidomide or a pharmaceutically acceptablesalt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof. Inone embodiment, provided herein is a mixture comprising (i) a cocrystalcomprising (a) pomalidomide or a pharmaceutically acceptable salt,solvate, hydrate, stereoisomer, prodrug, or clathrate thereof; and (b) acoformer, and (ii) an amorphous form of pomalidomide or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,prodrug, or clathrate thereof.

In one embodiment, provided herein is an unsolvated solid formcomprising (a) pomalidomide and (b) a coformer. In one embodiment,provided herein is an anhydrous solid form comprising (a) pomalidomideand (b) a coformer. In one embodiment, provided herein is an unsolvatedcrystal form comprising (a) pomalidomide and (b) a coformer. In oneembodiment, provided herein is an anhydrous crystal form comprising (a)pomalidomide and (b) a coformer. In one embodiment, provided herein isan unsolvated amorphous form comprising (a) pomalidomide and (b) acoformer. In one embodiment, provided herein is an anhydrous amorphousform comprising (a) pomalidomide and (b) a coformer. In one embodiment,provided herein is a solvated solid form comprising (a) pomalidomide and(b) a coformer. In one embodiment, provided herein is a hydrated solidform comprising (a) pomalidomide and (b) a coformer (e.g., a hydratehaving a stoichiometric or non-stoichiometric amount of water). In oneembodiment, provided herein is a hydrated form of (a) pomalidomide and(b) a coformer, including, but not limited to, a hemihydrate, amonohydrate, a dihydrate, a trihydrate, and the like. In one embodiment,the hydrated form is substantially crystalline. In one embodiment, thehydrated form is substantially amorphous. In one embodiment, theanhydrous form is substantially crystalline. In one embodiment, theanhydrous form is substantially amorphous. In one embodiment, providedherein is an unsolvated cocrystal comprising (a) pomalidomide and (b) acoformer. In one embodiment, provided herein is an anhydrous cocrystalcomprising (a) pomalidomide and (b) a coformer. In one embodiment,provided herein is a hydrated cocrystal comprising (a) pomalidomide and(b) a coformer. In one embodiment, provided herein is a solvatedcocrystal comprising (a) pomalidomide and (b) a coformer.

Solid forms provided herein can be prepared by the methods describedherein, or by techniques, including, but not limited to, heating,cooling, freeze drying, spray drying, lyophilization, quench cooling themelt, rapid solvent evaporation, slow solvent evaporation, solventrecrystallization, antisolvent addition, slurry recrystallization,crystallization from the melt, desolvation, recrystallization inconfined spaces, such as, e.g., in nanopores or capillaries,recrystallization on surfaces or templates, such as, e.g., on polymers,recrystallization in the presence of additives, such as, e.g.,co-crystal counter-molecules, desolvation, dehydration, rapid cooling,slow cooling, exposure to solvent and/or water, drying, including, e.g.,vacuum drying, vapor diffusion, sublimation, grinding (including, e.g.,cryo-grinding and solvent-drop grinding), microwave-inducedprecipitation, sonication-induced precipitation, laser-inducedprecipitation, and precipitation from a supercritical fluid. Theparticle size of the resulting solid forms, which can vary (e.g., fromnanometer dimensions to millimeter dimensions), can be controlled, e.g.,by varying crystallization conditions, such as, e.g., the rate ofcrystallization and/or the crystallization solvent system, or byparticle-size reduction techniques, e.g., grinding, milling,micronizing, or sonication.

In another embodiment, provided herein are compositions comprising oneor more solid form(s) comprising (a) pomalidomide or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathratethereof; and (b) a coformer. Also provided herein are compositionscomprising: (i) one or more solid form(s) provided herein (e.g., one ormore crystal forms, one or more amorphous forms, and mixtures thereof),and (ii) other active ingredient(s). Also provided herein are methods ofusing these compositions in the treatment, prevention, or management ofconditions and disorders including, but not limited to: cancer,including hematologic cancer or solid tumor, for example, multiplemyeloma, leukemia, lymphoma, sarcoma, prostate cancer, or small celllung cancer; scleroderma; amyloidosis; pain; myelofibrosis;myeloproliferative disease, e.g., MMM; myelodysplastic syndromes;diffuse systemic sclerosis; macular degeneration; a skin disease; apulmonary disorder, an asbestos-related disorder, a parasitic disease;an immunodeficiency disorder; a CNS disorder, a CNS injury;atherosclerosis; hemoglobinopathy; anemia, e.g., sickle cell anemia; aninflammatory disease; an autoimmune disease; a viral disease; a geneticdisease; an allergic disease; a bacterial disease; an ocular neovasculardisease; a choroidal neovascular disease; a retina neovascular disease;and rubeosis.

While not intending to be bound by any particular theory, certain solidforms provided herein exhibit physical properties, e.g., stability,solubility and/or dissolution rate, appropriate for use in clinical andtherapeutic dosage forms. Moreover, while not wishing to be bound by anyparticular theory, certain solid forms provided herein exhibit physicalproperties, e.g., crystal morphology, compressibility and/or hardness,suitable for manufacture of a solid dosage form. In some embodiments,such properties can be determined using techniques such as X-raydiffraction, microscopy, IR spectroscopy and thermal analysis, asdescribed herein and known in the art.

Certain embodiments herein provide solid forms comprising (a)pomalidomide and (b) a coformer. In one embodiment, provided herein is asolid form comprising (a) pomalidomide and (b) a coformer that issubstantially crystalline. In one embodiment, provided herein is acocrystal comprising (a) pomalidomide and (b) a coformer. In oneembodiment, provided herein is a solid form comprising a cocrystalcomprising (a) pomalidomide and (b) a coformer. In one embodiment,provided herein is a solid form comprising (i) a cocrystal comprising(a) pomalidomide and (b) a coformer and (ii) an amorphous form ofpomalidomide. In one embodiment, provided herein is a solid formcomprising (i) a cocrystal comprising (a) pomalidomide and (b) acoformer and (ii) one or more additional crystal forms of pomalidomide.

In some embodiments, the cocrystal comprising (a) pomalidomide and (b) acoformer can be obtained by crystallization from certain solventsystems, for example, solvent systems comprising one or more of thefollowing solvents: acetone, N,N-dimethylformamide (DMF),tetrahydrofuran (THF), and methanol. Other examples of solvent systemsare provided herein elsewhere. In certain embodiments, a solid formprovided herein (e.g., a cocrystal comprising (a) pomalidomide and (b) acoformer) can be obtained by slurry crystallization, evaporationcrystallization, cooling crystallization, and precipitationcrystallization.

In certain embodiments, the non-covalent forces are one or more hydrogenbonds (H-bonds). The coformer may be H-bonded directly to the API or maybe H-bonded to an additional molecule which is bound to the API. Theadditional molecule may be H-bonded to the API or bound ionically orcovalently to the API. The additional molecule could also be a differentAPI. In certain embodiments, the co-crystals may include one or moresolvate molecules in the crystalline lattice, i.e., solvates ofco-crystals, or a co-crystal further comprising a solvent or compoundthat is a liquid at room temperature. In certain embodiments, theco-crystals may be a co-crystal between a coformer and a salt of an API.In certain embodiments, the non-covalent forces are pi-stacking,guest-host complexation and/or van der Waals interactions. Hydrogenbonding can result in several different intermolecular configurations.For example, hydrogen bonds can result in the formation of dimers,linear chains, or cyclic structures. These configurations can furtherinclude extended (two-dimensional) hydrogen bond networks and isolatedtriads.

In certain embodiments, the coformer is a solid under ambienttemperature conditions when in its pure form. In certain embodiments,the coformer is selected from acetylsalicylic acid, D-glucose, nicotinicacid, aconitic acid, L-glutamic acid, oxalic acid, adipic acid, glutaricacid, L-proline, 4-aminosalicylic acid, glycine, propyl gallate,L-ascorbic acid, glycolic acid, L-pyroglutamic acid, benzoic acid,hippuric acid, saccharin, (+)-camphoric acid, 1-hydroxy-2-naphthoicacid, salicylic acid, capric acid, ketoglutaric acid, sebacic acid,cinnamic acid, L-lysine, sodium lauryl sulfate, citric acid, magnesiumbromide, sorbic acid, cyclamic acid, maleic acid, succinic acid, ethylmaltol, L-malic acid, L-tartaric acid, ethyl paraben, malonic acid,urea, D-fructose, maltol, vanillic acid, fumaric acid, D,L-mandelicacid, vanillin, gallic acid, methyl paraben, zinc chloride, gentisicacid, and nicotinamide. In certain embodiments, the coformer is a secondAPI.

In certain embodiments, the co-crystals include an acid addition salt orbase addition salt of an API. Acid addition salts include, but are notlimited to, inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, and phosphoric acid, and organic acids suchas acetic acid, propionic acid, hexanoic acid, heptanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartatic acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoicacid, cinnamic acid, madelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, p-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonicacid, 4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid),3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutaric acid, hydroxynaphthoicacid, salicylic acid, stearic acid, and muconic acid. Base additionsalts include, but are not limited to, inorganic bases such as sodium,potassium, lithium, ammonium, calcium and magnesium salts, and organicbases such as primary, secondary and tertiary amines (e.g.,isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine,tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine,lysine, arginine, histidine, procaine, hydrabamine, choline, betaine,ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines,piperazine, piperidine, morpholine, and N-ethylpiperidine).

The ratio of API to coformer may be stoichiometric ornon-stoichiometric. In one embodiment, the ratio of API to coformer isabout 5:1, 4:1, 3:1, 2.5:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3,1:4, or 1:5. In one embodiment, the ratio of API to coformer is about1:1. In one embodiment, the co-crystal comprises more than onecoformers. In one embodiment, the co-crystal comprises two coformers.

In certain embodiments, cocrystals can be prepared using solid-statemethods such as solid-state grinding and solvent-drop grinding. Incertain embodiments, cocrystals can be prepared using high-throughputscreening. In certain embodiments cocrystals can be prepared usingsolution-based crystallization.

In certain embodiments, cocrystals formation can lead to enhancement ofphysical properties of the resulting solid forms, such as solubility,dissolution rate, bioavailability, physical stability, chemicalstability, flowability, fractability, or compressibility. In certainembodiments, a given API may form different cocrystals with manydifferent counter-molecules, and some of these cocrystals may exhibitenhanced solubility or stability. In certain embodiments pharmaceuticalcocrystals increase the bioavailability or stability profile of acompound without the need for chemical (covalent) modification of theAPI.

The compounds provide herein may also contain an unnatural proportion ofan atomic isotope at one or more of the atoms that constitute such acompound. For example, the compound may be radiolabeled with radioactiveisotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) sulfur-35(³⁵S), or carbon-14 (¹⁴C). Radiolabeled compounds are useful astherapeutic agents, e.g., cancer therapeutic agents, research reagents,e.g., binding assay reagents, and diagnostic agents, e.g., in vivoimaging agents. All isotopic variations of the compounds providedherein, whether radioactive or not, are intended to be encompassedherein. In certain embodiments, a compound provided herein containsunnatural proportion(s) of one or more isotopes, including, but notlimited to, hydrogen (¹H), deuterium (²H), tritium (³H), carbon-11(¹¹C), carbon-12 (¹²C), carbon-13 (¹³C), carbon-14 (¹⁴C), nitrogen-13(¹³N), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N), oxygen-14 (¹⁴O), oxygen-15(¹⁵O), oxygen-16 (¹⁶O), oxygen-17 (¹⁷O), oxygen-18 (¹⁸O), fluorine-17(¹⁷F), fluorine-18 (¹⁸F), phosphorus-31 (³¹P), phosphorus-32 (³²P),phosphorus-33 (³³P), sulfur-32 (³²S), sulfur-33 (³³S), sulfur-34 (³⁴S),sulfur-35 (³⁵S), sulfur-36 (³⁶S), chlorine-35 (³⁵Cl), chlorine-36(³⁶Cl), chlorine-37 (³⁷Cl), bromine-79 (⁷⁹Br), bromine-81 (⁸¹Br),iodine-123 (¹²³I), iodine-125 (¹²⁵I), iodine-127 (¹²⁷I), iodine-129(¹²⁹I), and iodine-131 (¹³¹I). In certain embodiments, a compoundprovided herein contains unnatural proportion(s) of one or more isotopesin a stable form, that is, non-radioactive, including, but not limitedto, hydrogen (¹H), deuterium (²H), carbon-12 (¹²C), carbon-13 (¹³C),nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N), oxygen-16 (¹⁶O), oxygen-17 (¹⁷O),oxygen-18 (¹⁸O), fluorine-17 (¹⁷F), phosphorus-31 (³¹P), sulfur-32(³²S), sulfur-33 (³³S), sulfur-34 (³⁴S), sulfur-36 (³⁶S), chlorine-35(³⁵Cl), chlorine-37 (³⁷Cl), bromine-79 (⁷⁹Br), bromine-81 (⁸¹Br), andiodine-127 (¹²⁷I). In certain embodiments, a compound provided hereincontains unnatural proportion(s) of one or more isotopes in an unstableform, that is, radioactive, including, but not limited to, tritium (³H),carbon-11 (¹¹C), carbon-14 (¹⁴C), nitrogen-13 (¹³N), oxygen-14 (¹⁴O),oxygen-15 (¹⁵O), fluorine-18 (¹⁸F), phosphorus-32 (³²P), phosphorus-33(³³P), sulfur-35 (³⁵S), chlorine-36 (³⁶Cl), iodine-123 (¹²³I),iodine-125 (¹²⁵I), iodine-129 (¹²⁹I), and iodine-131 (¹³¹I). In certainembodiments, in a compound as provided herein, any hydrogen can be ²H,for example, or any carbon can be ¹³C, for example, or any nitrogen canbe ¹⁵N, for example, or any oxygen can be ¹⁸O, for example, wherefeasible according to the judgment of one of skill. In certainembodiments, a compound provided herein contains unnatural proportionsof deuterium (D). In exemplary embodiments, provided herein areisotopologues of pomalidomide, as disclosed in U.S. ProvisionalApplication No. 61/500,053, filed Jun. 22, 2011, which is incorporatedby reference herein in its entirety. In one embodiment, provided hereinare solid forms (e.g., crystal forms, amorphous forms, or mixturesthereof) of isotopologues of pomalidomide provided herein.

In certain embodiments, slurry crystallization is effected by addingsolvent or solvent mixtures to a solid substrate, and the slurry isstirred, and optionally heated to various temperatures. In certainembodiments, the slurry is heated at about 25° C., about 50° C., about80° C., or about 100° C. In certain embodiments, upon heating andcooling, the residual solvents of the slurry can be removed by wicking,or other suitable methods, such as filtration, centrifugation, ordecantation, and the crystals can be dried in air or under vacuum.

In certain embodiments, evaporation crystallization is effected byadding a solvent or solvent mixture to a solid substrate, and allowingthe solvent or solvent mixture to evaporate under ambient conditions. Incertain embodiments, the residual solvent can be removed by wicking, orother suitable methods, such as filtration, centrifugation, ordecantation, and the crystals can be dried in air or under vacuum.

In certain embodiments, precipitation crystallization is effected byadding a solvent or solvent mixture to a solid substrate, andsubsequently adding an anti-solvent. In certain embodiments, theresultant mixture stands for a period of time, e.g., overnight, andunder certain conditions, for example at room temperature. In certainembodiments, the residual solvent can be removed by wicking, or othersuitable methods, such as filtration, centrifugation, or decantation,and the crystals can be dried in air or under vacuum.

In certain embodiments, cooling crystallization is effected by adding asolvent or solvent mixture to a solid substrate at elevated temperature,and allowing the resultant mixture to stand for a period of time at areduced temperature. In certain embodiments, the elevated temperatureis, for example, about 30° C., about 40° C., about 50° C., about 60° C.,about 70° C., or about 80° C. In certain embodiments, the reducedtemperature is, for example, about 15° C., about 10° C., about 5° C.,about 0° C., about −5° C., about −10° C., about −15° C., or about −20°C. The residual solvent can be removed by wicking, or other suitablemethods, such as filtration, centrifugation, or decantation, and thecrystals can be dried in air or under vacuum.

5.2.1 Cocrystal Comprising Pomalidomide and Gallic Acid

Certain embodiments herein provide solid forms comprising pomalidomideand gallic acid. In one embodiment, provided herein is a solid formcomprising pomalidomide and gallic acid that is substantiallycrystalline. In one embodiment, provided herein is a cocrystalcomprising pomalidomide and gallic acid. In one embodiment, providedherein is a solid form comprising a cocrystal comprising pomalidomideand gallic acid. In one embodiment, provided herein is a solid formcomprising (i) a cocrystal comprising pomalidomide and gallic acid and(ii) an amorphous form of pomalidomide. In one embodiment, providedherein is a solid form comprising (i) a cocrystal comprisingpomalidomide and gallic acid and (ii) one or more additional crystalforms of pomalidomide. Provided herein are various embodiments,preparations, or modifications of a cocrystal comprising pomalidomideand gallic acid.

In some embodiments, the cocrystal comprising pomalidomide and gallicacid is obtained by mixing pomalidomide and gallic acid in a solventsystem. In some embodiments, the cocrystal is obtained by mixingpomalidomide and gallic acid in a solvent system saturated with gallicacid. In some embodiments, the cocrystal is obtained by mixingpomalidomide and gallic acid in a solvent system saturated with gallicacid, and subsequently stirring the mixture at room temperature forabout 24 hours. In some embodiments, the cocrystal is obtained by mixingpomalidomide and gallic acid in a solvent system saturated with gallicacid, subsequently stirring the mixture at room temperature for about 24hours, and isolating the solid by centrifugation. In some embodiments,the cocrystal is obtained by mixing approximately equal molar amount ofpomalidomide and gallic acid in a solvent system saturated with gallicacid. In some embodiments, the solvent system is a mixed solvent of DMFand acetone. In some embodiments, the solvent system is a mixed solventof DMF and acetone with a volumn ratio of DMF to acetone of about 1:2.

In some embodiments, the cocrystal comprising pomalidomide and gallicacid is obtained by removing solvent from a solution containingpomalidomide and gallic acid. In some embodiments, the cocrystal isobtained by removing solvent from a solution containing pomalidomide andgallic acid on a rotary evaporator at about 65° C. In some embodiments,the cocrystal is obtained by removing solvent from a solution containingpomalidomide and gallic acid, and subsequently storing the residue atabout 75% relative humidity for 1 day. In some embodiments, thecocrystal is obtained by removing solvent from a solution containingpomalidomide and gallic acid, and subsequently storing the residue atabout 60° C. overnight. In some embodiments, the cocrystal is obtainedby removing solvent from a solution containing approximately equal molaramount of pomalidomide and gallic acid. In some embodiments, the solventsystem is a mixed solvent of THF and water. In some embodiments, thesolvent system is a mixed solvent of THF and water with a volumn ratioof THF to water of about 95:5.

In some embodiments, provided herein is a cocrystal comprisingpomalidomide and gallic acid with a molar ratio of pomalidomide togallic acid of approximately 2:1 to 1:2. In some embodiments, the molarratio of pomalidomide to gallic acid is approximately 1:1.

A representative XRPD pattern of a solid form comprising pomalidomideand gallic acid is provided in FIG. 1. In some embodiments, providedherein is a solid form comprising pomalidomide and gallic acidcharacterized by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, or more peaks) selected from peakslocated at the following or approximately the following positions: 9.75,10.77, 11.75, 12.29, 12.73, 13.22, 14.06, 15.11, 15.52, 16.16, 16.59,16.94, 17.34, 18.42, 19.32, 19.38, 20.20, 21.52, 21.80, 22.98, 23.20,24.28, 24.82, 25.56, 26.16, 26.90, 27.99, 29.20, 30.40, 31.31, 32.06,32.59, 32.82, 33.87, 34.67, 35.10, 36.66, 37.16, 38.46, 39.24, and 39.78degrees 2θ, plus or minus 0.10. In some embodiments, provided herein isa solid form comprising pomalidomide and gallic acid characterized byone or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, or more peaks) selected from peaks located at the followingor approximately the following positions: 9.75, 10.77, 12.29, 14.06,15.52, 16.16, 17.34, 18.42, 22.98, 23.20, 24.82, 25.56, 26.16, 26.90,27.99, and 32.06 degrees 2θ, plus or minus 0.10. In some embodiments,the solid form is characterized by 3 of the peaks. In some embodiments,the solid form is characterized by 5 of the peaks. In some embodiments,the solid form is characterized by 7 of the peaks. In some embodiments,the solid form is characterized by 10 of the peaks. In some embodiments,the solid form is characterized by 13 of the peaks. In some embodiments,the solid form is characterized by all of the peaks.

In some embodiments, provided herein is a solid form comprisingpomalidomide and gallic acid having an XRPD pattern comprising peaks atapproximately 22.98, 26.16, and 26.90 degrees 2θ. In certainembodiments, the solid form further comprises peaks at approximately15.52, 18.42 and 23.20 degrees 2θ. In one embodiment, the solid formcomprises peaks at approximately 9.75, 10.77, 12.29, 14.06, 15.52,16.16, 17.34, 18.42, 22.98, 23.20, 24.82, 25.56, 26.16, 26.90, 27.99,and 32.06 degrees 2θ.

In some embodiments, provided herein is a solid form comprisingpomalidomide and gallic acid having an XRPD pattern comprising peaks atapproximately 15.52, 26.16, and 26.90 degrees 2θ. In some embodiments,provided herein is a solid form comprising pomalidomide and gallic acidhaving an XRPD pattern comprising peaks at approximately 18.42, 26.16,and 26.90 degrees 2θ. In some embodiments, provided herein is a solidform comprising pomalidomide and gallic acid having an XRPD patterncomprising peaks at approximately 23.20, 26.16, and 26.90 degrees 2θ.

In some embodiments, the XRPD peaks above (degrees 2θ peaks) are whenanalyzed using copper Kα radiation. In some embodiments, provided hereinis a solid form comprising pomalidomide and gallic acid, wherein thesolid form is characterized by an XRPD diffraction pattern which matchesthe XRPD pattern presented in FIG. 1.

5.2.2 Cocrystal Comprising Pomalidomide and Vanillin

Certain embodiments herein provide solid forms comprising pomalidomideand vanillin. In one embodiment, provided herein is a solid formcomprising pomalidomide and vanillin that is substantially crystalline.In one embodiment, provided herein is a cocrystal comprisingpomalidomide and vanillin. In one embodiment, provided herein is a solidform comprising a cocrystal comprising pomalidomide and vanillin. In oneembodiment, provided herein is a solid form comprising (i) a cocrystalcomprising pomalidomide and vanillin and (ii) an amorphous form ofpomalidomide. In one embodiment, provided herein is a solid formcomprising (i) a cocrystal comprising pomalidomide and vanillin and (ii)one or more additional crystal forms of pomalidomide. Provided hereinare various embodiments, preparations, or modifications of a cocrystalcomprising pomalidomide and vanillin.

In some embodiments, the cocrystal comprising pomalidomide and vanillinis obtained by grinding pomalidomide and vanillin together in thepresence of a minor quantity of a solvent system. In some embodiments,the cocrystal comprising pomalidomide and vanillin is obtained bygrinding approximately equal molar amount of pomalidomide and vanillintogether in the presence of a minor quantity of a solvent system. Insome embodiments, the solvent system is acetone.

In some embodiments, the cocrystal comprising pomalidomide and vanillinis obtained by removing solvent from a solution containing pomalidomideand vanillin. In some embodiments, the cocrystal is obtained by removingsolvent from a solution containing pomalidomide and vanillin on a rotaryevaporator at about 65° C. In some embodiments, the cocrystal isobtained by removing solvent from a solution containing pomalidomide andvanillin, and subsequently storing the residue at about 75% relativehumidity for 1 day. In some embodiments, the cocrystal is obtained byremoving solvent from a solution containing pomalidomide and vanillin,and subsequently storing the residue at about 60° C. overnight. In someembodiments, the cocrystal is obtained by removing solvent from asolution containing approximately equal molar amount of pomalidomide andvanillin. In some embodiments, the solvent system is a mixed solvent ofTHF and water. In some embodiments, the solvent system is a mixedsolvent of THF and water with a volumn ratio of THF to water of about95:5.

In some embodiments, provided herein is a cocrystal comprisingpomalidomide and vanillin with a molar ratio of pomalidomide to vanillinof approximately 2:1 to 1:2. In some embodiments, the molar ratio ofpomalidomide to vanillin is approximately 1:1.

A representative XRPD pattern of a solid form comprising pomalidomideand vanillin is provided in FIG. 2. In some embodiments, provided hereinis a solid form comprising pomalidomide and vanillin characterized byone or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, or more peaks) selected from peakslocated at the following or approximately the following positions:11.68, 12.25, 12.73, 13.09, 14.02, 14.45, 15.44, 16.22, 16.91, 17.30,18.40, 19.22, 20.04, 21.10, 21.58, 21.76, 22.63, 22.95, 23.53, 23.87,24.33, 24.85, 25.61, 25.96, 26.66, 26.89, 28.01, 29.35, 31.96, 32.91,33.91, 34.93, and 35.65 degrees 2θ, plus or minus 0.10. In someembodiments, provided herein is a solid form comprising pomalidomide andvanillin characterized by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or morepeaks) selected from peaks located at the following or approximately thefollowing positions: 11.68, 12.25, 12.73, 13.09, 14.02, 15.44, 16.22,16.91, 17.30, 18.40, 22.95, 24.33, 24.85, 25.61, 25.96, 26.66, 26.89,28.01, 29.35, 31.96, and 33.91 degrees 2θ, plus or minus 0.10. In someembodiments, the solid form is characterized by 3 of the peaks. In someembodiments, the solid form is characterized by 5 of the peaks. In someembodiments, the solid form is characterized by 7 of the peaks. In someembodiments, the solid form is characterized by 10 of the peaks. In someembodiments, the solid form is characterized by 13 of the peaks. In someembodiments, the solid form is characterized by all of the peaks.

In some embodiments, provided herein is a solid form comprisingpomalidomide and vanillin having an XRPD pattern comprising peaks atapproximately 13.09, 17.30, and 25.61 degrees 2θ. In certainembodiments, the solid form further comprises peaks at approximately12.25, 16.91, and 28.01 degrees 2θ. In one embodiment, the solid formcomprises peaks at approximately 11.68, 12.25, 12.73, 13.09, 14.02,15.44, 16.22, 16.91, 17.30, 18.40, 22.95, 24.33, 24.85, 25.61, 25.96,26.66, 26.89, 28.01, 29.35, 31.96, and 33.91 degrees 2θ.

In some embodiments, provided herein is a solid form comprisingpomalidomide and vanillin having an XRPD pattern comprising peaks atapproximately 13.09, 12.25, and 25.61 degrees 2θ. In some embodiments,provided herein is a solid form comprising pomalidomide and vanillinhaving an XRPD pattern comprising peaks at approximately 13.09, 16.91,and 25.61 degrees 2θ. In some embodiments, provided herein is a solidform comprising pomalidomide and vanillin having an XRPD patterncomprising peaks at approximately 13.09, 28.01, and 25.61 degrees 2θ.

In some embodiments, the XRPD peaks above (degrees 2θ peaks) are whenanalyzed using copper Kα radiation. In some embodiments, provided hereinis a solid form comprising pomalidomide and vanillin, wherein the solidform is characterized by an XRPD diffraction pattern which matches theXRPD pattern presented in FIG. 2.

5.2.3 Cocrystal Comprising Pomalidomide and Cyclamic Acid

Certain embodiments herein provide solid forms comprising pomalidomideand cyclamic acid. In one embodiment, provided herein is a solid formcomprising pomalidomide and cyclamic acid that is substantiallycrystalline. In one embodiment, provided herein is a cocrystalcomprising pomalidomide and cyclamic acid. In one embodiment, providedherein is a solid form comprising a cocrystal comprising pomalidomideand cyclamic acid. In one embodiment, provided herein is a solid formcomprising (i) a cocrystal comprising pomalidomide and cyclamic acid and(ii) an amorphous form of pomalidomide. In one embodiment, providedherein is a solid form comprising (i) a cocrystal comprisingpomalidomide and cyclamic acid and (ii) one or more additional crystalforms of pomalidomide. Provided herein are various embodiments,preparations, or modifications of a cocrystal comprising pomalidomideand cyclamic acid.

In some embodiments, the cocrystal comprising pomalidomide and cyclamicacid is obtained by mixing pomalidomide and cyclamic acid in a solventsystem. In some embodiments, the cocrystal is obtained by mixingpomalidomide and cyclamic acid in a solvent system saturated withcyclamic acid. In some embodiments, the cocrystal is obtained by mixingpomalidomide and cyclamic acid in a solvent system saturated withcyclamic acid, and subsequently stirring the mixture at room temperaturefor about 24 hours. In some embodiments, the cocrystal is obtained bymixing pomalidomide and cyclamic acid in a solvent system saturated withcyclamic acid, subsequently stirring the mixture at room temperature forabout 24 hours, and isolating the solid by centrifugation. In someembodiments, the cocrystal is obtained by mixing approximately equalmolar amount of pomalidomide and cyclamic acid in a solvent systemsaturated with cyclamic acid. In some embodiments, the solvent system isa mixed solvent of DMF and acetone with a volumn ratio of DMF to acetoneof about 1:2.

In some embodiments, provided herein is a cocrystal comprisingpomalidomide and cyclamic acid with a molar ratio of pomalidomide tocyclamic acid of approximately 2:1 to 1:2. In some embodiments, themolar ratio of pomalidomide to cyclamic acid is approximately 1:1.

A representative XRPD pattern of a solid form comprising pomalidomideand cyclamic acid is provided in FIG. 3. In some embodiments, providedherein is a solid form comprising pomalidomide and cyclamic acidcharacterized by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, or more peaks) selected from peaks located at the following orapproximately the following positions: 5.78, 6.42, 7.10, 7.88, 12.18,12.81, 14.03, 15.73, 16.23, 17.31, 18.30, 18.54, 18.66, 19.25, 20.26,21.27, 21.66, 23.69, 24.45, 25.49, 26.00, 26.80, 27.72, 28.08, 28.64,30.30, 31.18, 32.32, 33.16, 34.93, 37.07, 37.47, and 39.02 degrees 2θ,plus or minus 0.10. In some embodiments, provided herein is a solid formcomprising pomalidomide and cyclamic acid characterized by one or moreXRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks) selectedfrom peaks located at the following or approximately the followingpositions: 6.42, 7.88, 15.73, 18.30, 18.54, 19.25, 21.27, 21.66, 25.49,and 33.16 degrees 2θ, plus or minus 0.10. In some embodiments, the solidform is characterized by 3 of the peaks. In some embodiments, the solidform is characterized by 5 of the peaks. In some embodiments, the solidform is characterized by 7 of the peaks. In some embodiments, the solidform is characterized by all of the peaks.

In some embodiments, provided herein is a solid form comprisingpomalidomide and cyclamic acid having an XRPD pattern comprising peaksat approximately 6.42 and 7.88 degrees 2θ. In some embodiments, providedherein is a solid form comprising pomalidomide and cyclamic acid havingan XRPD pattern comprising peaks at approximately 6.42, 7.88, and 15.73degrees 2θ. In certain embodiments, the solid form further comprisespeaks at approximately 18.54 and 19.25 degrees 2θ. In one embodiment,the solid form comprises peaks at approximately 6.42, 7.88, 15.73,18.30, 18.54, 19.25, 21.27, 21.66, 25.49, and 33.16 degrees 2θ.

In some embodiments, provided herein is a solid form comprisingpomalidomide and cyclamic acid having an XRPD pattern comprising peaksat approximately 6.42, 7.88, and 18.54 degrees 2θ. In some embodiments,provided herein is a solid form comprising pomalidomide and cyclamicacid having an XRPD pattern comprising peaks at approximately 6.42,7.88, and 19.25 degrees 2θ.

In some embodiments, the XRPD peaks above (degrees 2θ peaks) are whenanalyzed using copper Kα radiation. In some embodiments, provided hereinis a solid form comprising pomalidomide and cyclamic acid, wherein thesolid form is characterized by an XRPD diffraction pattern which matchesthe XRPD pattern presented in FIG. 3.

5.2.4 Cocrystal Comprising Pomalidomide and D-Glucose

Certain embodiments herein provide solid forms comprising pomalidomideand D-glucose. In one embodiment, provided herein is a solid formcomprising pomalidomide and D-glucose that is substantially crystalline.In one embodiment, provided herein is a cocrystal comprisingpomalidomide and D-glucose. In one embodiment, provided herein is asolid form comprising a cocrystal comprising pomalidomide and D-glucose.In one embodiment, provided herein is a solid form comprising (i) acocrystal comprising pomalidomide and D-glucose and (ii) an amorphousform of pomalidomidc. In one embodiment, provided herein is a solid formcomprising (i) a cocrystal comprising pomalidomide and D-glucose and(ii) one or more additional crystal forms of pomalidomide. Providedherein are various embodiments, preparations, or modifications of acocrystal comprising pomalidomide and D-glucose.

In some embodiments, the cocrystal comprising pomalidomide and D-glucoseis obtained by mixing pomalidomide and D-glucose in a solvent system. Insome embodiments, the cocrystal is obtained by mixing pomalidomide andD-glucose in a solvent system saturated with D-glucose. In someembodiments, the cocrystal is obtained by mixing pomalidomide andD-glucose in a solvent system saturated with D-glucose, and subsequentlystirring the mixture at room temperature for about 24 hours. In someembodiments, the cocrystal is obtained by mixing pomalidomide andD-glucose in a solvent system saturated with D-glucose, subsequentlystirring the mixture at room temperature for about 24 hours, andisolating the solid by centrifugation. In some embodiments, thecocrystal is obtained by mixing approximately equal molar amount ofpomalidomide and D-glucose in a solvent system saturated with D-glucose.In some embodiments, the solvent system is a mixed solvent of DMF andmethanol with a volumn ratio of DMF to methanol of about 1:1.

In some embodiments, provided herein is a cocrystal comprisingpomalidomide and D-glucose with a molar ratio of pomalidomide toD-glucose of approximately 2:1 to 1:2. In some embodiments, the molarratio of pomalidomide to D-glucose is approximately 1:1.

A representative XRPD pattern of a solid form comprising pomalidomideand D-glucose is provided in FIG. 4. In some embodiments, providedherein is a solid form comprising pomalidomide and D-glucosecharacterized by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or more peaks) selected from peaks located at thefollowing or approximately the following positions: 5.27, 10.44, 11.84,12.31, 12.72, 14.08, 14.70, 16.18, 16.54, 17.09, 17.35, 18.43, 18.80,19.31, 19.76, 20.20, 20.68, 22.85, 23.13, 24.31, 24.79, 25.52, 26.81,27.57, 28.00, 28.47, 29.20, 30.01, 30.72, 31.29, 31.65, 32.05, 33.92,34.60, 34.75, 35.14, 36.06, 36.26, 36.56, 37.60, 39.14, 39.34, 39.62,and 39.95 degrees 2θ, plus or minus 0.10. In some embodiments, providedherein is a solid form comprising pomalidomide and D-glucosecharacterized by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or more peaks) selected from peaks located at thefollowing or approximately the following positions: 11.84, 12.31, 14.08,17.09, 17.35, 18.43, 18.80, 20.68, 24.31, 24.79, 25.52, 28.00, 28.47,and 29.20 degrees 2θ, plus or minus 0.10. In some embodiments, the solidform is characterized by 3 of the peaks. In some embodiments, the solidform is characterized by 5 of the peaks. In some embodiments, the solidform is characterized by 7 of the peaks. In some embodiments, the solidform is characterized by 10 of the peaks. In some embodiments, the solidform is characterized by all of the peaks.

In some embodiments, provided herein is a solid form comprisingpomalidomide and D-glucose having an XRPD pattern comprising peaks atapproximately 17.09, 20.68, and 25.52 degrees 2θ. In certainembodiments, the solid form further comprises peaks at approximately12.31, 14.08, and 17.35 degrees 2θ. In one embodiment, the solid formcomprises peaks at approximately 11.84, 12.31, 14.08, 17.09, 17.35,18.43, 18.80, 20.68, 24.31, 24.79, 25.52, 28.00, 28.47, and 29.20degrees 2θ.

In some embodiments, provided herein is a solid form comprisingpomalidomide and D-glucose having an XRPD pattern comprising peaks atapproximately 12.31, 20.68, and 25.52 degrees 2θ. In some embodiments,provided herein is a solid form comprising pomalidomide and D-glucosehaving an XRPD pattern comprising peaks at approximately 14.08, 20.68,and 25.52 degrees 2θ. In some embodiments, provided herein is a solidform comprising pomalidomide and D-glucose having an XRPD patterncomprising peaks at approximately 17.35, 20.68, and 25.52 degrees 2θ.

In some embodiments, the XRPD peaks above (degrees 2θ peaks) are whenanalyzed using copper Kα radiation. In some embodiments, provided hereinis a solid form comprising pomalidomide and D-glucose, wherein the solidform is characterized by an XRPD diffraction pattern which matches theXRPD pattern presented in FIG. 4.

5.2.5 Cocrystal Comprising Pomalidomide and Propyl Gallate

Certain embodiments herein provide solid forms comprising pomalidomideand propyl gallate. In one embodiment, provided herein is a solid formcomprising pomalidomide and propyl gallate that is substantiallycrystalline. In one embodiment, provided herein is a cocrystalcomprising pomalidomide and propyl gallate. In one embodiment, providedherein is a solid form comprising a cocrystal comprising pomalidomideand propyl gallate. In one embodiment, provided herein is a solid formcomprising (i) a cocrystal comprising pomalidomide and propyl gallateand (ii) an amorphous form of pomalidomide. In one embodiment, providedherein is a solid form comprising (i) a cocrystal comprisingpomalidomide and propyl gallate and (ii) one or more additional crystalforms of pomalidomide. Provided herein are various embodiments,preparations, or modifications of a cocrystal comprising pomalidomideand propyl gallate.

In some embodiments, the cocrystal comprising pomalidomide and propylgallate is obtained by mixing pomalidomide and propyl gallate in asolvent system. In some embodiments, the cocrystal is obtained by mixingpomalidomide and propyl gallate in a solvent system saturated withpropyl gallate. In some embodiments, the cocrystal is obtained by mixingpomalidomide and propyl gallate in a solvent system saturated withpropyl gallate, and subsequently stirring the mixture at roomtemperature for about 24 hours. In some embodiments, the cocrystal isobtained by mixing pomalidomide and propyl gallate in a solvent systemsaturated with propyl gallate, subsequently stirring the mixture at roomtemperature for about 24 hours, and isolating the solid bycentrifugation. In some embodiments, the cocrystal is obtained by mixingapproximately equal molar amount of pomalidomide and propyl gallate in asolvent system saturated with propyl gallate. In some embodiments, thesolvent system is a mixed solvent of DMF and methanol with a volumnratio of DMF to methanol of about 1:1.

In some embodiments, provided herein is a cocrystal comprisingpomalidomide and propyl gallate with a molar ratio of pomalidomide topropyl gallate of approximately 2:1 to 1:2. In some embodiments, themolar ratio of pomalidomide to propyl gallate is approximately 1:1.

A representative XRPD pattern of a solid form comprising pomalidomideand propyl gallate is provided in FIG. 5. In some embodiments, providedherein is a solid form comprising pomalidomide and propyl gallatecharacterized by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, or more peaks) selected from peaks located at thefollowing or approximately the following positions: 4.88, 7.23, 7.78,8.87, 9.46, 11.36, 11.75, 12.29, 12.76, 13.30, 14.08, 15.52, 16.19,16.54, 16.97, 17.03, 17.35, 18.25, 18.42, 18.90, 19.35, 19.80, 22.89,23.33, 24.29, 25.23, 25.61, 27.71, 28.02, 28.39, 29.26, 32.17, 33.95,and 35.80 degrees 2θ, plus or minus 0.10. In some embodiments, providedherein is a solid form comprising pomalidomide and propyl gallatecharacterized by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, or more peaks) selected from peaks located at thefollowing or approximately the following positions: 7.78, 12.29, 12.76,14.08, 16.97, 17.35, 18.42, 24.29, 25.23, 25.61, 28.02, 29.26, and 32.17degrees 2θ, plus or minus 0.10. In some embodiments, the solid form ischaracterized by 3 of the peaks. In some embodiments, the solid form ischaracterized by 5 of the peaks. In some embodiments, the solid form ischaracterized by 7 of the peaks. In some embodiments, the solid form ischaracterized by 10 of the peaks. In some embodiments, the solid form ischaracterized by all of the peaks.

In some embodiments, provided herein is a solid form comprisingpomalidomide and propyl gallate having an XRPD pattern comprising peaksat approximately 7.78, 25.23, and 25.61 degrees 2θ. In certainembodiments, the solid form further comprises peaks at approximately17.35 and 24.29 degrees 2θ. In certain embodiments, the solid formfurther comprises peaks at approximately 12.29 and 14.08 degrees 2θ. Inone embodiment, the solid form comprises peaks at approximately 7.78,12.29, 12.76, 14.08, 16.97, 17.35, 18.42, 24.29, 25.23, 25.61, 28.02,29.26, and 32.17 degrees 2θ.

In some embodiments, provided herein is a solid form comprisingpomalidomide and propyl gallate having an XRPD pattern comprising peaksat approximately 7.78, 12.29, 25.23, and 25.61 degrees 2θ. In someembodiments, provided herein is a solid form comprising pomalidomide andpropyl gallate having an XRPD pattern comprising peaks at approximately7.78, 14.08, 25.23, and 25.61 degrees 2θ. In some embodiments, providedherein is a solid form comprising pomalidomide and propyl gallate havingan XRPD pattern comprising peaks at approximately 7.78, 17.35, 25.23,and 25.61 degrees 2θ. In some embodiments, provided herein is a solidform comprising pomalidomide and propyl gallate having an XRPD patterncomprising peaks at approximately 7.78, 24.29, 25.23, and 25.61 degrees2θ.

In some embodiments, the XRPD peaks above (degrees 2θ peaks) are whenanalyzed using copper Kα radiation. In some embodiments, provided hereinis a solid form comprising pomalidomide and propyl gallate, wherein thesolid form is characterized by an XRPD diffraction pattern which matchesthe XRPD pattern presented in FIG. 5.

5.2.6 Cocrystal Comprising Pomalidomide and Saccharin

Certain embodiments herein provide solid forms comprising pomalidomideand saccharin. In one embodiment, provided herein is a solid formcomprising pomalidomide and saccharin that is substantially crystalline.In one embodiment, provided herein is a cocrystal comprisingpomalidomide and saccharin. In one embodiment, provided herein is asolid form comprising a cocrystal comprising pomalidomide and saccharin.In one embodiment, provided herein is a solid form comprising (i) acocrystal comprising pomalidomide and saccharin and (ii) an amorphousform of pomalidomide. In one embodiment, provided herein is a solid formcomprising (i) a cocrystal comprising pomalidomide and saccharin and(ii) one or more additional crystal forms of pomalidomide. Providedherein are various embodiments, preparations, or modifications of acocrystal comprising pomalidomide and saccharin.

In some embodiments, the cocrystal comprising pomalidomide and saccharinis obtained by mixing pomalidomide and saccharin in a solvent system. Insome embodiments, the cocrystal is obtained by mixing pomalidomide andsaccharin in a solvent system saturated with saccharin. In someembodiments, the cocrystal is obtained by mixing pomalidomide andsaccharin in a solvent system saturated with saccharin, and subsequentlystirring the mixture at room temperature for about 24 hours. In someembodiments, the cocrystal is obtained by mixing pomalidomide andsaccharin in a solvent system saturated with saccharin, subsequentlystirring the mixture at room temperature for about 24 hours, andisolating the solid by centrifugation. In some embodiments, thecocrystal is obtained by mixing approximately equal molar amount ofpomalidomide and saccharin in a solvent system saturated with saccharin.In some embodiments, the solvent system is a mixed solvent of DMF andmethanol with a volumn ratio of DMF to methanol of about 1:1.

In some embodiments, provided herein is a cocrystal comprisingpomalidomide and saccharin with a molar ratio of pomalidomide tosaccharin of approximately 2:1 to 1:2. In some embodiments, the molarratio of pomalidomide to saccharin is approximately 1:1.

A representative XRPD pattern of a solid form comprising pomalidomideand saccharin is provided in FIG. 6. In some embodiments, providedherein is a solid form comprising pomalidomide and saccharincharacterized by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, or more peaks) selected from peakslocated at the following or approximately the following positions: 8.52,9.53, 11.75, 12.31, 12.71, 13.48, 14.07, 14.91, 15.39, 15.98, 16.50,16.94, 17.36, 18.44, 19.09, 20.07, 21.51, 22.80, 23.61, 23.80, 24.33,24.99, 25.10, 25.53, 25.73, 26.24, 27.38, 27.95, 28.44, 28.80, 29.15,29.38, 30.48, 30.83, 32.02, 32.28, 33.72, 34.27, 34.97, 37.90, and 38.33degrees 2θ, plus or minus 0.10. In some embodiments, provided herein isa solid form comprising pomalidomide and saccharin characterized by oneor more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, or more peaks) selected from peaks located at the followingor approximately the following positions: 12.31, 13.48, 14.07, 15.98,16.94, 17.36, 18.44, 19.09, 20.07, 22.80, 23.80, 24.33, 25.10, 25.53,25.73, 27.38, and 27.95 degrees 2θ, plus or minus 0.10. In someembodiments, the solid form is characterized by 3 of the peaks. In someembodiments, the solid form is characterized by 5 of the peaks. In someembodiments, the solid form is characterized by 7 of the peaks. In someembodiments, the solid form is characterized by 10 of the peaks. In someembodiments, the solid form is characterized by 13 of the peaks. In someembodiments, the solid form is characterized by all of the peaks.

In some embodiments, provided herein is a solid form comprisingpomalidomide and saccharin having an XRPD pattern comprising peaks atapproximately 15.98, 19.09, and 25.10 degrees 2θ. In certainembodiments, the solid form further comprises peaks at approximately20.07 and 25.73 degrees 2θ. In certain embodiments, the solid formfurther comprises peaks at approximately 17.36 and 25.53 degrees 2θ. Inone embodiment, the solid form comprises peaks at approximately 12.31,13.48, 14.07, 15.98, 16.94, 17.36, 18.44, 19.09, 20.07, 22.80, 23.80,24.33, 25.10, 25.53, 25.73, 27.38, and 27.95 degrees 2θ.

In some embodiments, provided herein is a solid form comprisingpomalidomidc and saccharin having an XRPD pattern comprising peaks atapproximately 15.98, 17.36, and 25.10 degrees 2θ. In some embodiments,provided herein is a solid form comprising pomalidomide and saccharinhaving an XRPD pattern comprising peaks at approximately 15.98, 20.07,and 25.10 degrees 2θ. In some embodiments, provided herein is a solidform comprising pomalidomide and saccharin having an XRPD patterncomprising peaks at approximately 15.98, 25.10, and 25.53 degrees 2θ. Insome embodiments, provided herein is a solid form comprisingpomalidomide and saccharin having an XRPD pattern comprising peaks atapproximately 15.98, 25.10, and 25.73 degrees 2θ.

In some embodiments, the XRPD peaks above (degrees 2θ peaks) are whenanalyzed using copper Kα radiation. In some embodiments, provided hereinis a solid form comprising pomalidomide and saccharin, wherein the solidform is characterized by an XRPD diffraction pattern which matches theXRPD pattern presented in FIG. 6.

5.2.7 Cocrystal Comprising Pomalidomide and Sodium Lauryl Sulfate

Certain embodiments herein provide solid forms comprising pomalidomideand sodium lauryl sulfate. In one embodiment, provided herein is a solidform comprising pomalidomide and sodium lauryl sulfate that issubstantially crystalline. In one embodiment, provided herein is acocrystal comprising pomalidomide and sodium lauryl sulfate. In oneembodiment, provided herein is a solid form comprising a cocrystalcomprising pomalidomide and sodium lauryl sulfate. In one embodiment,provided herein is a solid form comprising (i) a cocrystal comprisingpomalidomide and sodium lauryl sulfate and (ii) an amorphous form ofpomalidomide. In one embodiment, provided herein is a solid formcomprising (i) a cocrystal comprising pomalidomide and sodium laurylsulfate and (ii) one or more additional crystal forms of pomalidomide.Provided herein are various embodiments, preparations, or modificationsof a cocrystal comprising pomalidomide and sodium lauryl sulfate.

In some embodiments, the cocrystal comprising pomalidomide and sodiumlauryl sulfate is obtained by grinding pomalidomide and sodium laurylsulfate together in the presence of a minor quantity of a solventsystem. In some embodiments, the cocrystal comprising pomalidomide andsodium lauryl sulfate is obtained by grinding approximately equal molaramount of pomalidomide and sodium lauryl sulfate together in thepresence of a minor quantity of a solvent system. In some embodiments,the solvent system is a mixed solvent of acetone and methanol. In oneembodiment, the solvent system is a mixed solvent of acetone andmethanol with a volumn ratio of acetone to methanol of about 1:1.

In some embodiments, provided herein is a cocrystal comprisingpomalidomide and sodium lauryl sulfate with a molar ratio ofpomalidomide to sodium lauryl sulfate of approximately 2:1 to 1:2. Insome embodiments, the molar ratio of pomalidomide to sodium laurylsulfate is approximately 1:1.

A representative XRPD pattern of a solid form comprising pomalidomideand sodium lauryl sulfate is provided in FIG. 7. In some embodiments,provided herein is a solid form comprising pomalidomide and sodiumlauryl sulfate characterized by one or more XRPD peaks (e.g., 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or more peaks)selected from peaks located at the following or approximately thefollowing positions: 2.20, 2.66, 4.36, 5.30, 6.53, 7.93, 10.62, 12.20,12.68, 13.26, 14.00, 16.16, 16.90, 17.27, 18.35, 20.37, 20.66, 20.98,21.42, 21.71, 22.86, 24.29, 24.75, 25.53, 26.72, 27.98, 29.19, 32.07,and 33.88 degrees 2θ, plus or minus 0.10. In some embodiments, providedherein is a solid form comprising pomalidomide and sodium lauryl sulfatecharacterized by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or more peaks) selected frompeaks located at the following or approximately the following positions:2.20, 2.66, 4.36, 5.30, 7.93, 10.62, 12.20, 13.26, 14.00, 16.90, 17.27,18.35, 20.66, 21.42, 24.29, 24.75, 25.53, 27.98, and 29.19 degrees 2θ,plus or minus 0.10. In some embodiments, the solid form is characterizedby 3 of the peaks. In some embodiments, the solid form is characterizedby 5 of the peaks. In some embodiments, the solid form is characterizedby 7 of the peaks. In some embodiments, the solid form is characterizedby 10 of the peaks. In some embodiments, the solid form is characterizedby 13 of the peaks. In some embodiments, the solid form is characterizedby all of the peaks.

In some embodiments, provided herein is a solid form comprisingpomalidomide and sodium lauryl sulfate having an XRPD pattern comprisingpeaks at approximately 2.66, 5.30, and 7.93 degrees 2θ. In certainembodiments, the solid form further comprises a peak at approximately2.20 degrees 2θ. In certain embodiments, the solid form furthercomprises peaks at approximately 12.20, 17.27, and 25.53 degrees 2θ. Inone embodiment, the solid form comprises peaks at approximately 2.20,2.66, 4.36, 5.30, 7.93, 10.62, 12.20, 13.26, 14.00, 16.90, 17.27, 18.35,20.66, 21.42, 24.29, 24.75, 25.53, 27.98, and 29.19 degrees 2θ.

In some embodiments, the XRPD peaks above (degrees 2θ peaks) are whenanalyzed using copper Kα radiation. In some embodiments, provided hereinis a solid form comprising pomalidomide and sodium lauryl sulfate,wherein the solid form is characterized by an XRPD diffraction patternwhich matches the XRPD pattern presented in FIG. 7.

5.2.8 Cocrystal Comprising Pomalidomide and Magnesium Bromide

Certain embodiments herein provide solid forms comprising pomalidomideand magnesium bromide. In one embodiment, provided herein is a solidform comprising pomalidomide and magnesium bromide that is substantiallycrystalline. In one embodiment, provided herein is a cocrystalcomprising pomalidomide and magnesium bromide. In one embodiment,provided herein is a solid form comprising a cocrystal comprisingpomalidomide and magnesium bromide. In one embodiment, provided hereinis a solid form comprising (i) a cocrystal comprising pomalidomide andmagnesium bromide and (ii) an amorphous form of pomalidomide. In oneembodiment, provided herein is a solid form comprising (i) a cocrystalcomprising pomalidomide and magnesium bromide and (ii) one or moreadditional crystal forms of pomalidomide. Provided herein are variousembodiments, preparations, or modifications of a cocrystal comprisingpomalidomide and magnesium bromide.

In some embodiments, the cocrystal comprising pomalidomide and magnesiumbromide is obtained by removing solvent from a solution containingpomalidomide and magnesium bromide. In some embodiments, the cocrystalis obtained by removing solvent from a solution containing pomalidomideand magnesium bromide on a rotary evaporator at about 65° C. In someembodiments, the cocrystal is obtained by removing solvent from asolution containing pomalidomide and magnesium bromide, and subsequentlystoring the residue at about 75% relative humidity for 1 day. In someembodiments, the cocrystal is obtained by removing solvent from asolution containing pomalidomide and magnesium bromide, and subsequentlystoring the residue at about 60° C. overnight. In some embodiments, thecocrystal is obtained by removing solvent from a solution containingapproximately equal molar amount of pomalidomide and magnesium bromide.In some embodiments, the solvent system is a mixed solvent of THF andwater. In some embodiments, the solvent system is a mixed solvent of THFand water with a volumn ratio of THF to water of about 95:5.

In some embodiments, provided herein is a cocrystal comprisingpomalidomide and magnesium bromide with a molar ratio of pomalidomide tomagnesium bromide of approximately 2:1 to 1:2. In some embodiments, themolar ratio of pomalidomide to magnesium bromide is approximately 1:1.

A representative XRPD pattern of a solid form comprising pomalidomideand magnesium bromide is provided in FIG. 8. In some embodiments,provided herein is a solid form comprising pomalidomide and magnesiumbromide characterized by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more peaks) selected from peakslocated at the following or approximately the following positions: 3.23,11.91, 12.79, 13.95, 14.74, 16.21, 16.60, 17.16, 18.38, 20.10, 24.28,24.80, 25.72, 28.58, 28.76, 29.87, 29.95, 32.08, and 32.79 degrees 2θ,plus or minus 0.10. In some embodiments, provided herein is a solid formcomprising pomalidomide and magnesium bromide characterized by one ormore XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, or more peaks) selected from peaks located at the following orapproximately the following positions: 3.23, 11.91, 13.95, 14.74, 16.60,17.16, 18.38, 20.10, 24.28, 24.80, 25.72, 28.58, 28.76, 29.87, 29.95,and 32.79 degrees 2θ, plus or minus 0.10. In some embodiments, the solidform is characterized by 3 of the peaks. In some embodiments, the solidform is characterized by 5 of the peaks. In some embodiments, the solidform is characterized by 7 of the peaks. In some embodiments, the solidform is characterized by 10 of the peaks. In some embodiments, the solidform is characterized by 13 of the peaks. In some embodiments, the solidform is characterized by all of the peaks.

In some embodiments, provided herein is a solid form comprisingpomalidomide and magnesium bromide having an XRPD pattern comprisingpeaks at approximately 3.23, 28.76, and 29.95 degrees 2θ. In certainembodiments, the solid form further comprises peaks at approximately25.72 and 29.87 degrees 2θ. In certain embodiments, the solid formfurther comprises peaks at approximately 17.16 and 28.58 degrees 2θ. Inone embodiment, the solid form comprises peaks at approximately 3.23,11.91, 13.95, 14.74, 16.60, 17.16, 18.38, 20.10, 24.28, 24.80, 25.72,28.58, 28.76, 29.87, 29.95, and 32.79 degrees 2θ.

In some embodiments, provided herein is a solid form comprisingpomalidomide and magnesium bromide having an XRPD pattern comprisingpeaks at approximately 17.16, 28.76, and 29.95 degrees 2θ. In someembodiments, provided herein is a solid form comprising pomalidomide andmagnesium bromide having an XRPD pattern comprising peaks atapproximately 25.72, 28.76, and 29.95 degrees 2θ. In some embodiments,provided herein is a solid form comprising pomalidomide and magnesiumbromide having an XRPD pattern comprising peaks at approximately 28.58,28.76, and 29.95 degrees 2θ. In some embodiments, provided herein is asolid form comprising pomalidomide and magnesium bromide having an XRPDpattern comprising peaks at approximately 28.76, 29.87, and 29.95degrees 2θ.

In some embodiments, the XRPD peaks above (degrees 2θ peaks) are whenanalyzed using copper Kα radiation. In some embodiments, provided hereinis a solid form comprising pomalidomide and magnesium bromide, whereinthe solid form is characterized by an XRPD diffraction pattern whichmatches the XRPD pattern presented in FIG. 8.

5.2.9 Cocrystal Comprising Pomalidomide and Malonic Acid

Certain embodiments herein provide solid forms comprising pomalidomideand malonic acid. In one embodiment, provided herein is a solid formcomprising pomalidomide and malonic acid that is substantiallycrystalline. In one embodiment, provided herein is a cocrystalcomprising pomalidomide and malonic acid. In one embodiment, providedherein is a solid form comprising a cocrystal comprising pomalidomideand malonic acid. In one embodiment, provided herein is a solid formcomprising (i) a cocrystal comprising pomalidomide and malonic acid and(ii) an amorphous form of pomalidomide. In one embodiment, providedherein is a solid form comprising (i) a cocrystal comprisingpomalidomide and malonic acid and (ii) one or more additional crystalforms of pomalidomide. Provided herein are various embodiments,preparations, or modifications of a cocrystal comprising pomalidomideand malonic acid.

In some embodiments, the cocrystal comprising pomalidomide and malonicacid is obtained by removing solvent from a solution containingpomalidomide and malonic acid. In some embodiments, the cocrystal isobtained by removing solvent from a solution containing pomalidomide andmalonic acid on a rotary evaporator at about 65° C. In some embodiments,the cocrystal is obtained by removing solvent from a solution containingpomalidomide and malonic acid, and subsequently storing the residue atabout 75% relative humidity for 1 day. In some embodiments, thecocrystal is obtained by removing solvent from a solution containingpomalidomide and malonic acid, and subsequently storing the residue atabout 60° C. overnight. In some embodiments, the cocrystal is obtainedby removing solvent from a solution containing approximately equal molaramount of pomalidomide and malonic acid. In some embodiments, thesolvent system is a mixed solvent of THF and water. In some embodiments,the solvent system is a mixed solvent of THF and water with a volumnratio of THF to water of about 95:5.

In some embodiments, provided herein is a cocrystal comprisingpomalidomide and malonic acid with a molar ratio of pomalidomide tomalonic acid of approximately 2:1 to 1:2. In some embodiments, the molarratio of pomalidomide to malonic acid is approximately 1:1.

A representative XRPD pattern of a solid form comprising pomalidomideand malonic acid is provided in FIG. 9. In some embodiments, providedherein is a solid form comprising pomalidomide and malonic acidcharacterized by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or more peaks)selected from peaks located at the following or approximately thefollowing positions: 12.23, 12.73, 13.99, 16.18, 16.63, 17.27, 18.37,18.81, 19.18, 20.42, 21.83, 22.44, 23.34, 23.79, 24.29, 24.85, 25.58,27.98, 28.44, 29.33, 30.96, 31.34, 32.58, 33.08, 33.90, 35.28, 37.36,38.08, 38.59, and 39.43 degrees 2θ, plus or minus 0.10. In someembodiments, provided herein is a solid form comprising pomalidomide andmalonic acid characterized by one or more XRPD peaks (e.g., 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or morepeaks) selected from peaks located at the following or approximately thefollowing positions: 12.23, 12.73, 13.99, 16.18, 16.63, 17.27, 18.37,21.83, 22.44, 23.34, 23.79, 24.29, 24.85, 25.58, 27.98, 28.44, 29.33,30.96, 32.58, 33.90, and 37.36 degrees 2θ, plus or minus 0.10. In someembodiments, the solid form is characterized by 3 of the peaks. In someembodiments, the solid form is characterized by 5 of the peaks. In someembodiments, the solid form is characterized by 7 of the peaks. In someembodiments, the solid form is characterized by 10 of the peaks. In someembodiments, the solid form is characterized by 13 of the peaks. In someembodiments, the solid form is characterized by all of the peaks.

In some embodiments, provided herein is a solid form comprisingpomalidomide and malonic acid having an XRPD pattern comprising peaks atapproximately 12.23, 16.63, and 25.58 degrees 2θ. In certainembodiments, the solid form further comprises peaks at approximately17.27 and 24.29 degrees 2θ. In certain embodiments, the solid formfurther comprises peaks at approximately 13.99, 23.34, and 27.98 degrees2θ. In one embodiment, the solid form comprises peaks at approximately12.23, 12.73, 13.99, 16.18, 16.63, 17.27, 18.37, 21.83, 22.44, 23.34,23.79, 24.29, 24.85, 25.58, 27.98, 28.44, 29.33, 30.96, 32.58, 33.90,and 37.36 degrees 2θ.

In some embodiments, provided herein is a solid form comprisingpomalidomide and malonic acid having an XRPD pattern comprising peaks atapproximately 13.99, 16.63, and 25.58 degrees 2θ. In some embodiments,provided herein is a solid form comprising pomalidomide and malonic acidhaving an XRPD pattern comprising peaks at approximately 16.63, 17.27,and 25.58 degrees 2θ. In some embodiments, provided herein is a solidform comprising pomalidomide and malonic acid having an XRPD patterncomprising peaks at approximately 16.63, 23.34, and 25.58 degrees 2θ. Insome embodiments, provided herein is a solid form comprisingpomalidomide and malonic acid having an XRPD pattern comprising peaks atapproximately 16.63, 24.29, and 25.58 degrees 2θ. In some embodiments,provided herein is a solid form comprising pomalidomide and malonic acidhaving an XRPD pattern comprising peaks at approximately 16.63, 25.58,and 27.98 degrees 2θ.

In some embodiments, the XRPD peaks above (degrees 2θ peaks) are whenanalyzed using copper Kα radiation. In some embodiments, provided hereinis a solid form comprising pomalidomide and malonic acid, wherein thesolid form is characterized by an XRPD diffraction pattern which matchesthe XRPD pattern presented in FIG. 9.

5.2.10 Cocrystal Comprising Pomalidomide and Maltol

Certain embodiments herein provide solid forms comprising pomalidomideand maltol. In one embodiment, provided herein is a solid formcomprising pomalidomide and maltol that is substantially crystalline. Inone embodiment, provided herein is a cocrystal comprising pomalidomideand maltol. In one embodiment, provided herein is a solid formcomprising a cocrystal comprising pomalidomide and maltol. In oneembodiment, provided herein is a solid form comprising (i) a cocrystalcomprising pomalidomide and maltol and (ii) an amorphous form ofpomalidomide. In one embodiment, provided herein is a solid formcomprising (i) a cocrystal comprising pomalidomide and maltol and (ii)one or more additional crystal forms of pomalidomide. Provided hereinare various embodiments, preparations, or modifications of a cocrystalcomprising pomalidomide and maltol.

In some embodiments, the cocrystal comprising pomalidomide and maltol isobtained by removing solvent from a solution containing pomalidomide andmaltol. In some embodiments, the cocrystal is obtained by removingsolvent from a solution containing pomalidomide and maltol on a rotaryevaporator at about 65° C. In some embodiments, the cocrystal isobtained by removing solvent from a solution containing pomalidomide andmaltol, and subsequently storing the residue at about 75% relativehumidity for 1 day. In some embodiments, the cocrystal is obtained byremoving solvent from a solution containing pomalidomide and maltol, andsubsequently storing the residue at about 60° C. overnight. In someembodiments, the cocrystal is obtained by removing solvent from asolution containing approximately equal molar amount of pomalidomide andmaltol. In some embodiments, the solvent system is a mixed solvent ofTHF and water. In some embodiments, the solvent system is a mixedsolvent of THF and water with a volumn ratio of THF to water of about95:5.

In some embodiments, provided herein is a cocrystal comprisingpomalidomide and maltol with a molar ratio of pomalidomide to maltol ofapproximately 2:1 to 1:2. In some embodiments, the molar ratio ofpomalidomide to maltol is approximately 1:1.

A representative XRPD pattern of a solid form comprising pomalidomideand maltol is provided in FIG. 10. In some embodiments, provided hereinis a solid form comprising pomalidomide and maltol characterized by oneor more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, or more peaks) selected from peaks located at the following orapproximately the following positions: 11.41, 11.87, 12.75, 13.93,14.54, 14.78, 16.51, 17.09, 18.34, 19.72, 22.98, 24.25, 24.74, 25.73,26.33, 27.00, 27.91, 28.50, 29.46, 29.86, 30.17, 32.14, 33.17, 33.98,34.97, and 35.66 degrees 2θ, plus or minus 0.10. In some embodiments,provided herein is a solid form comprising pomalidomide and maltolcharacterized by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, or more peaks) selected from peakslocated at the following or approximately the following positions:11.87, 13.93, 14.54, 14.78, 16.51, 17.09, 18.34, 24.25, 24.74, 25.73,26.33, 27.00, 27.91, 28.50, 29.46, and 32.14 degrees 2θ, plus or minus0.10. In some embodiments, the solid form is characterized by 3 of thepeaks. In some embodiments, the solid form is characterized by 5 of thepeaks. In some embodiments, the solid form is characterized by 7 of thepeaks. In some embodiments, the solid form is characterized by 10 of thepeaks. In some embodiments, the solid form is characterized by 13 of thepeaks. In some embodiments, the solid form is characterized by all ofthe peaks.

In some embodiments, provided herein is a solid form comprisingpomalidomide and maltol having an XRPD pattern comprising peaks atapproximately 16.51, 17.09, and 25.73 degrees 2θ. In certainembodiments, the solid form further comprises peaks at approximately13.93 and 24.25 degrees 2θ. In certain embodiments, the solid formfurther comprises peaks at approximately 11.87 and 14.54 degrees 2θ. Inone embodiment, the solid form comprises peaks at approximately 11.87,13.93, 14.54, 14.78, 16.51, 17.09, 18.34, 24.25, 24.74, 25.73, 26.33,27.00, 27.91, 28.50, 29.46, and 32.14 degrees 2θ.

In some embodiments, provided herein is a solid form comprisingpomalidomide and maltol having an XRPD pattern comprising peaks atapproximately 11.87, 17.09, and 25.73 degrees 2θ. In some embodiments,provided herein is a solid form comprising pomalidomide and maltolhaving an XRPD pattern comprising peaks at approximately 13.93, 17.09,and 25.73 degrees 2θ. In some embodiments, provided herein is a solidform comprising pomalidomide and maltol having an XRPD patterncomprising peaks at approximately 14.54, 17.09, and 25.73 degrees 2θ. Insome embodiments, provided herein is a solid form comprisingpomalidomide and maltol having an XRPD pattern comprising peaks atapproximately 17.09, 24.25, and 25.73 degrees 2θ.

In some embodiments, the XRPD peaks above (degrees 2θ peaks) are whenanalyzed using copper Kα radiation. In some embodiments, provided hereinis a solid form comprising pomalidomide and maltol, wherein the solidform is characterized by an XRPD diffraction pattern which matches theXRPD pattern presented in FIG. 10.

5.2.11 Cocrystal Comprising Pomalidomide and Methyl Paraben

Certain embodiments herein provide solid forms comprising pomalidomideand methyl paraben. In one embodiment, provided herein is a solid formcomprising pomalidomide and methyl paraben that is substantiallycrystalline. In one embodiment, provided herein is a cocrystalcomprising pomalidomide and methyl paraben. In one embodiment, providedherein is a solid form comprising a cocrystal comprising pomalidomideand methyl paraben. In one embodiment, provided herein is a solid formcomprising (i) a cocrystal comprising pomalidomide and methyl parabenand (ii) an amorphous form of pomalidomide. In one embodiment, providedherein is a solid form comprising (i) a cocrystal comprisingpomalidomide and methyl paraben and (ii) one or more additional crystalforms of pomalidomide. Provided herein are various embodiments,preparations, or modifications of a cocrystal comprising pomalidomideand methyl paraben.

In some embodiments, the cocrystal comprising pomalidomide and methylparaben is obtained by removing solvent from a solution containingpomalidomide and methyl paraben. In some embodiments, the cocrystal isobtained by removing solvent from a solution containing pomalidomide andmethyl paraben on a rotary evaporator at about 65° C. In someembodiments, the cocrystal is obtained by removing solvent from asolution containing pomalidomide and methyl paraben, and subsequentlystoring the residue at about 75% relative humidity for 1 day. In someembodiments, the cocrystal is obtained by removing solvent from asolution containing pomalidomide and methyl paraben, and subsequentlystoring the residue at about 60° C. overnight. In some embodiments, thecocrystal is obtained by removing solvent from a solution containingapproximately equal molar amount of pomalidomide and methyl paraben. Insome embodiments, the solvent system is a mixed solvent of THF andwater. In some embodiments, the solvent system is a mixed solvent of THFand water with a volumn ratio of THF to water of about 95:5.

In some embodiments, provided herein is a cocrystal comprisingpomalidomide and methyl paraben with a molar ratio of pomalidomide tomethyl paraben of approximately 2:1 to 1:2. In some embodiments, themolar ratio of pomalidomide to methyl paraben is approximately 1:1.

A representative XRPD pattern of a solid form comprising pomalidomideand methyl paraben is provided in FIG. 11. In some embodiments, providedherein is a solid form comprising pomalidomide and methyl parabencharacterized by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, or more peaks) selected from peakslocated at the following or approximately the following positions:10.46, 10.61, 11.38, 11.88, 12.70, 13.90, 14.71, 16.50, 17.10, 18.33,18.73, 19.77, 21.00, 21.27, 21.75, 21.90, 21.98, 23.00, 23.95, 24.28,24.38, 24.50, 25.69, 26.70, 27.85, 28.49, 29.01, 29.10, 30.14, 30.82,32.10, 32.62, 33.09, 33.98, 34.77, and 36.87 degrees 2θ, plus or minus0.10. In some embodiments, provided herein is a solid form comprisingpomalidomide and methyl paraben characterized by one or more XRPD peaks(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or morepeaks) selected from peaks located at the following or approximately thefollowing positions: 10.46, 10.61, 11.88, 13.90, 14.71, 16.50, 17.10,18.33, 18.73, 19.77, 21.27, 21.98, 24.28, 24.38, 24.50, 25.69, 26.70,28.49, and 29.01 degrees 2θ, plus or minus 0.10. In some embodiments,the solid form is characterized by 3 of the peaks. In some embodiments,the solid form is characterized by 5 of the peaks. In some embodiments,the solid form is characterized by 7 of the peaks. In some embodiments,the solid form is characterized by 10 of the peaks. In some embodiments,the solid form is characterized by 13 of the peaks. In some embodiments,the solid form is characterized by all of the peaks.

In some embodiments, provided herein is a solid form comprisingpomalidomide and methyl paraben having an XRPD pattern comprising peaksat approximately 18.73, 25.69, and 26.70 degrees 2θ. In certainembodiments, the solid form further comprises peaks at approximately13.90 and 21.98 degrees 2θ. In certain embodiments, the solid formfurther comprises peaks at approximately 17.10, 24.38, and 29.01 degrees2θ. In one embodiment, the solid form comprises peaks at approximately10.46, 10.61, 11.88, 13.90, 14.71, 16.50, 17.10, 18.33, 18.73, 19.77,21.27, 21.98, 24.28, 24.38, 24.50, 25.69, 26.70, 28.49, and 29.01degrees 2θ.

In some embodiments, provided herein is a solid form comprisingpomalidomide and methyl paraben having an XRPD pattern comprising peaksat approximately 18.73, 21.98, and 26.70 degrees 2θ. In someembodiments, provided herein is a solid form comprising pomalidomide andmethyl paraben having an XRPD pattern comprising peaks at approximately14.71, 21.98, and 26.70 degrees 2θ. In some embodiments, provided hereinis a solid form comprising pomalidomide and methyl paraben having anXRPD pattern comprising peaks at approximately 21.98, 26.70, and 29.01degrees 2θ.

In some embodiments, the XRPD peaks above (degrees 2θ peaks) are whenanalyzed using copper Kα radiation. In some embodiments, provided hereinis a solid form comprising pomalidomide and methyl paraben, wherein thesolid form is characterized by an XRPD diffraction pattern which matchesthe XRPD pattern presented in FIG. 11.

5.2.12 Cocrystal Comprising Pomalidomide and Zinc Chloride

Certain embodiments herein provide solid forms comprising pomalidomideand zinc chloride. In one embodiment, provided herein is a solid formcomprising pomalidomide and zinc chloride that is substantiallycrystalline. In one embodiment, provided herein is a cocrystalcomprising pomalidomide and zinc chloride. In one embodiment, providedherein is a solid form comprising a cocrystal comprising pomalidomideand zinc chloride. In one embodiment, provided herein is a solid formcomprising (i) a cocrystal comprising pomalidomide and zinc chloride and(ii) an amorphous form of pomalidomide. In one embodiment, providedherein is a solid form comprising (i) a cocrystal comprisingpomalidomide and zinc chloride and (ii) one or more additional crystalforms of pomalidomide. Provided herein are various embodiments,preparations, or modifications of a cocrystal comprising pomalidomideand zinc chloride.

In some embodiments, the cocrystal comprising pomalidomide and zincchloride is obtained by removing solvent from a solution containingpomalidomide and zinc chloride. In some embodiments, the cocrystal isobtained by removing solvent from a solution containing pomalidomide andzinc chloride on a rotary evaporator at about 65° C. In someembodiments, the cocrystal is obtained by removing solvent from asolution containing pomalidomide and zinc chloride, and subsequentlystoring the residue at about 75% relative humidity for 1 day. In someembodiments, the cocrystal is obtained by removing solvent from asolution containing pomalidomide and zinc chloride, and subsequentlystoring the residue at about 60° C. overnight. In some embodiments, thecocrystal is obtained by removing solvent from a solution containingapproximately equal molar amount of pomalidomide and zinc chloride. Insome embodiments, the solvent system is a mixed solvent of THF andwater. In some embodiments, the solvent system is a mixed solvent of THFand water with a volumn ratio of THF to water of about 95:5.

In some embodiments, provided herein is a cocrystal comprisingpomalidomide and zinc chloride with a molar ratio of pomalidomide tozinc chloride of approximately 2:1 to 1:2. In some embodiments, themolar ratio of pomalidomide to zinc chloride is approximately 1:1.

A representative XRPD pattern of a solid form comprising pomalidomideand zinc chloride is provided in FIG. 12. In some embodiments, providedherein is a solid form comprising pomalidomide and zinc chloridecharacterized by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, or more peaks) selected from peaks located atthe following or approximately the following positions: 2.38, 2.93,3.22, 11.95, 12.77, 13.97, 16.61, 17.17, 18.37, 23.03, 24.00, 24.30,24.79, 25.71, 27.90, 28.56, and 29.53 degrees 2θ, plus or minus 0.10. Insome embodiments, provided herein is a solid form comprisingpomalidomide and zinc chloride characterized by one or more XRPD peaks(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more peaks)selected from peaks located at the following or approximately thefollowing positions: 2.38, 2.93, 3.22, 11.95, 13.97, 16.61, 17.17,18.37, 23.03, 24.00, 24.30, 24.79, 25.71, 27.90, and 28.56 degrees 2θ,plus or minus 0.10. In some embodiments, the solid form is characterizedby 3 of the peaks. In some embodiments, the solid form is characterizedby 5 of the peaks. In some embodiments, the solid form is characterizedby 7 of the peaks. In some embodiments, the solid form is characterizedby 10 of the peaks. In some embodiments, the solid form is characterizedby 13 of the peaks. In some embodiments, the solid form is characterizedby all of the peaks.

In some embodiments, provided herein is a solid form comprisingpomalidomide and zinc chloride having an XRPD pattern comprising peaksat approximately 2.38, 17.17, and 25.71 degrees 2θ. In certainembodiments, the solid form further comprises peaks at approximately3.22 and 16.61 degrees 2θ. In certain embodiments, the solid formfurther comprises peaks at approximately 11.95 and 28.56 degrees 2θ. Inone embodiment, the solid form comprises peaks at approximately 2.38,2.93, 3.22, 11.95, 13.97, 16.61, 17.17, 18.37, 23.03, 24.00, 24.30,24.79, 25.71, 27.90, and 28.56 degrees 2θ.

In some embodiments, provided herein is a solid form comprisingpomalidomide and zinc chloride having an XRPD pattern comprising peaksat approximately 2.38, 3.22, and 25.71 degrees 2θ. In some embodiments,provided herein is a solid form comprising pomalidomide and zincchloride having an XRPD pattern comprising peaks at approximately 2.38,11.95, and 25.71 degrees 2θ. In some embodiments, provided herein is asolid form comprising pomalidomide and zinc chloride having an XRPDpattern comprising peaks at approximately 2.38, 16.61, and 25.71 degrees2θ. In some embodiments, provided herein is a solid form comprisingpomalidomide and zinc chloride having an XRPD pattern comprising peaksat approximately 2.38, 25.71, and 28.56 degrees 2θ.

In some embodiments, the XRPD peaks above (degrees 2θ peaks) are whenanalyzed using copper Kα radiation. In some embodiments, provided hereinis a solid form comprising pomalidomide and zinc chloride, wherein thesolid form is characterized by an XRPD diffraction pattern which matchesthe XRPD pattern presented in FIG. 12.

5.2.13 Polymorphs of Pomalidomide

Certain embodiments herein provide solid forms comprising pomalidomide.In one embodiment, provided herein is a solid form of pomalidomide thatis substantially crystalline. In one embodiment, provided herein is acrystal form of pomalidomide. In one embodiment, provided herein is asolid form of pomalidomide comprising crystalline pomalidomide.

In certain embodiments, provided herein are solid forms of pomalidomidethat can be designated herein as Form A. Form A of pomalidomide has beendescribed in International Patent Application No. PCT/US2013/026662, theentirety of which is incorporated herein by reference. A representativeXRPD pattern of a solid form comprising pomalidomide is provided in FIG.13A.

In certain embodiments, provided herein are solid forms of pomalidomidethat can be designated herein as Form B. In some embodiments, the solidform comprising Form B of pomalidomide is obtained by removing solventfrom a solution containing pomalidomide, with or without the presence ofa coformer. In some embodiments, the solid form is obtained by removingsolvent from a solution containing pomalidomide on a rotary evaporatorat about 65° C. In some embodiments, the solid form is obtained byremoving solvent from a solution containing pomalidomide, andsubsequently storing the residue at about 75% relative humidity for 1day. In some embodiments, the solid form is obtained by removing solventfrom a solution containing pomalidomide, and subsequently storing theresidue at about 60° C. overnight. In some embodiments, the solventsystem is a mixed solvent of THF and water. In some embodiments, thesolvent system is a mixed solvent of THF and water with a volumn ratioof THF to water of about 95:5.

A representative XRPD pattern of a solid form comprising pomalidomide isprovided in FIG. 13B. In some embodiments, the XRPD peaks above (degrees2θ peaks) are when analyzed using copper Kα radiation. In someembodiments, provided herein is a solid form comprising pomalidomide,wherein the solid form is characterized by an XRPD diffraction patternwhich matches the XRPD pattern presented in FIG. 13B.

A representative thermal gravimetric analysis (TGA) curve of a solidform comprising pomalidomide is provided in FIG. 14, which exhibits aweight loss of about 1.20% of the total sample weight upon heating fromabout 25 to about 100° C. In some embodiments, provided herein is asolid form comprising pomalidomide, wherein the solid form ischaracterized by a TGA thermogram which matches the TGA thermogrampresented in FIG. 14.

A representative differential scanning calorimetry (DSC) thermogram of asolid form comprising pomalidomide is presented in FIG. 14. In someembodiments, provided herein is a solid form comprising pomalidomidethat exhibits a thermal event, as characterized by DSC, with a peaktemperature of about 316° C. and/or an onset temperature of about 315°C. In some embodiments, provided herein is a solid form comprisingpomalidomide, wherein the solid form is characterized by a DSCthermogram which matches the DSC thermogram presented in FIG. 14.

In one embodiment, Form B of pomalidomide converts to Form A ofpomalidomide after slurring in EtOH, 0.1 N HCl, or water for 3 days. Inone embodiment, without being limited by particular theory, Form B is ametastable form of pomalidomide.

In certain embodiments, provided herein are solid form comprising (i) acocrystal comprising (a) pomalidomide or a pharmaceutically acceptablesalt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof; and(b) a coformer, and (ii) a crystal form of pomalidomide or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,prodrug, or clathrate thereof. In one embodiment, the crystal form ofpomalidomide is Form A. In another embodiment, the crystal form ofpomalidomide is Form B.

In one embodiment, provided herein is a solid form comprising (i) acocrystal comprising pomalidomide and gallic acid; and (ii) Form A ofpomalidomide.

In one embodiment, provided herein is a solid form comprising (i) acocrystal comprising pomalidomide and vanillin; and (ii) Form A ofpomalidomide.

In one embodiment, provided herein is a solid form comprising (i) acocrystal comprising pomalidomide and D-glucose; and (ii) Form A ofpomalidomide.

In one embodiment, provided herein is a solid form comprising (i) acocrystal comprising pomalidomide and propyl gallate; and (ii) Form A ofpomalidomide.

In one embodiment, provided herein is a solid form comprising (i) acocrystal comprising pomalidomide and saccharin; and (ii) Form A ofpomalidomide.

In one embodiment, provided herein is a solid form comprising (i) acocrystal comprising pomalidomide and sodium lauryl sulfate; and (ii)Form A of pomalidomide.

In one embodiment, provided herein is a solid form comprising (i) acocrystal comprising pomalidomide and malonic acid; and (ii) Form A ofpomalidomide.

In one embodiment, provided herein is a solid form comprising (i) acocrystal comprising pomalidomide and gallic acid; and (ii) Form B ofpomalidomide.

In one embodiment, provided herein is a solid form comprising (i) acocrystal comprising pomalidomide and magnesium bromide; and (ii) Form Bof pomalidomide.

In one embodiment, provided herein is a solid form comprising (i) acocrystal comprising pomalidomide and maltol; and (ii) Form B ofpomalidomide.

In one embodiment, provided herein is a solid form comprising (i) acocrystal comprising pomalidomide and methyl paraben; and (ii) Form B ofpomalidomide.

In one embodiment, provided herein is a solid form comprising (i) acocrystal comprising pomalidomide and vanillin; and (ii) Form B ofpomalidomide.

In one embodiment, provided herein is a solid form comprising (i) acocrystal comprising pomalidomide and zinc chloride; and (ii) Form B ofpomalidomide.

5.3 Methods of Treatment, Prevention and Management

Provided herein are methods of treating, preventing, and/or managingvarious diseases or disorders using a solid form provided herein. Incertain embodiments, provided are methods of treating, managing, andpreventing various diseases and disorders, which comprise administeringto a patient in need of such treatment, prevention or management atherapeutically or prophylactically effective amount of a solid formprovided herein. Examples of diseases and disorders are describedherein.

Examples of diseases or disorders include, but are not limited to:cancer, including hematologic cancer or solid tumor, for example,multiple myeloma, leukemia, lymphoma, sarcoma, prostate cancer, or lungcancer (e.g., small cell lung cancer); scleroderma; amyloidosis; pain,for example, complex regional pain syndrome (CRPS); myelofibrosis;myeloproliferative disease, for example, MMM; myelodysplastic syndromes(MDS); diffuse systemic sclerosis; macular degeneration; a skin disease;a pulmonary disorder; an asbestos-related disorder; a parasitic disease;an immunodeficiency disorder; a CNS disorder; a CNS injury;atherosclerosis; hemoglobinopathy; anemia, for example, sickle cellanemia; an inflammatory disease; an autoimmune disease; a viral disease;a genetic disease; an allergic disease; a bacterial disease; an ocularneovascular disease; a choroidal neovascular disease; a retinaneovascular disease; rubeosis; a sleep disorder; disorders associatedwith angiogenesis; and TNFα related disorders.

Examples of cancer and precancerous conditions include, but are notlimited to, those described in U.S. Pat. Nos. 6,281,230 and 5,635,517 toMuller et al., in various U.S. patent publications to Zeldis, includingpublication nos. 2004/0220144A1, published Nov. 4, 2004 (Treatment ofMyelodysplastic Syndrome); 2004/0029832A1, published Feb. 12, 2004(Treatment of Various Types of Cancer); and 2004/0087546, published May6, 2004 (Treatment of Myeloproliferative Diseases). Examples alsoinclude those described in WO 2004/103274, published Dec. 2, 2004. Allof these references are incorporated herein in their entireties byreference.

Other examples of diseases or disorders include, but are not limited to,those described in U.S. Pat. Nos. 5,712,291, 7,393,863, and 7,863,297;and U.S. Patent Application Publication Nos. 2005/0143420, 2006/0166932,2006/0188475, 2007/0048327, 2007/0066512, 2007/0155791, 2008/0051431,2008/0317708, 2009/0087407, 2009/0088410, 2009/0148853, 2009/0232776,2009/0232796, 2009/0317385, 2010/0098657, 2010/0099711, and2011/0184025; all of which are incorporated herein by reference in theirentireties.

In one embodiment is provided a method of treating, preventing and/ormanaging a disease provided herein, comprising administering to apatient in need of such treatment, prevention and/or management atherapeutically or prophylactically effective amount of a solid formcomprising pomalidomide and a coformer as described herein and atherapeutically or prophylactically effective amount of a second activeagent.

Examples of second active agents include, but are not limited to,cytokines, corticosteroids, ribonucleotide reductase inhibitors,platelet inhibitors, all-trans retinoic acids, kinase inhibitors,topoisomerase inhibitors, farnesyl transferase inhibitors, antisenseoligonucleotides, vaccines, anti-cancer agents, anti-fungal agents,anti-inflammatory agents, immunosuppressive or myelosuppressive agents,and conventional therapies for MPD (e.g., prednisone). Specific secondactive agents include, but are not limited to, 2-methoxyestradiol,telomestatin, inducers of apoptosis in multiple myeloma cells (such as,for example, TRAIL), statins, semaxanib, cyclosporin, etanercept,doxycycline, bortezomib, oblimersen (Genasense®), remicade, docetaxel,celecoxib, melphalan, dexamethasone (Decadron®), steroids, gemcitabine,cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar,carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate,Arisa®, taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda,CPT-11, interferon alpha, pegylated interferon alpha (e.g., PEGINTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin,liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine,IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate,biaxin, busulphan, prednisone, bisphosphonate, arsenic trioxide,vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin,estramustine sodium phosphate (Emcyt®), sulindac, etoposide, and amixture thereof. In one embodiment, specific second active agent isdexamethasone.

Certain examples of cancer include, but are not limited to, cancers ofthe skin, such as melanoma; lymph node; breast; cervix; uterus;gastrointestinal tract; lung; ovary; prostate; colon; rectum; mouth;brain; head and neck; throat; testes; kidney; pancreas; bone; spleen;liver; bladder; larynx; nasal passages; and AIDS-related cancers. Thesolid forms are also useful for treating cancers of the blood and bonemarrow, such as multiple myeloma and acute and chronic leukemias, forexample, lymphoblastic, myelogenous, lymphocytic, and myelocyticleukemias. The solid forms provided herein can be used for treating,preventing, or managing either primary or metastatic tumors.

Other cancers include, but are not limited to, advanced malignancy,amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiplebrain metastases, glioblastoma multiforms, glioblastoma, brain stemglioma, poor prognosis malignant brain tumor, malignant glioma,recurrent malignant glioma, anaplastic astrocytoma, anaplasticoligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C& D colorectal cancer, unresectable colorectal carcinoma, metastatichepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblasticleukemia, chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma,non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Celllymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma,metastatic melanoma, localized melanoma (including, but not limited to,ocular melanoma), malignant mesothelioma, malignant pleural effusionmesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma,gynecologic sarcoma, soft tissue sarcoma, cutaneous vasculitis,Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificansprogressive, hormone refractory prostate cancer, resected high-risk softtissue sarcoma, unresectable hepatocellular carcinoma, Waldenstrom'smacroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tubecancer, androgen independent prostate cancer, androgen dependent stageIV non-metastatic prostate cancer, hormone-insensitive prostate cancer,chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma,follicular thyroid carcinoma, medullary thyroid carcinoma, andleiomyoma. In a specific embodiment, the cancer is metastatic. Inanother embodiment, the cancer is refractory or resistance tochemotherapy or radiation.

In one embodiment is provided a method of treating, preventing, ormanaging myeloproliferative disease (MPD), comprising administering to apatient in need of such treatment, prevention, or management atherapeutically or prophylactically effective amount of a solid formcomprising pomalidomide and a coformer as described herein. Theembodiment encompasses the treatment, prevention or management ofspecific sub-types of MPD such as, but not limited to, polycythemiarubra vera (PRV), primary thrombocythemia (PT), myelofibrosis withmyeloid metaplasia (MMM) and agnogenic myeloid metaplasia (AMM). In oneembodiment, MPD includes: polycythemia rubra vera (PRV), primarythrombocythemia (PT), and agnogenic myeloid metaplasia (AMM). In aspecific embodiment, MPD excludes leukemia. In one embodiment,particular types of MPD are MMM, PRV, PT, and AMM.

In one embodiment, a solid form comprising pomalidomide and a coformeris administered to patients who are refractory to conventionaltreatments for myeloproliferative diseases as well as treatments usingthalidomide. As used herein, the term “refractory” means the patient'sresponse to a MPD treatment is not satisfactory by clinical standards,e.g., showing no or little improvement of symptoms or laboratoryfindings.

In one embodiment is provided a method of reversing, reducing, oravoiding an adverse effect associated with the administration of anactive agent used to treat MPD in a patient suffering from MPD,comprising administering to a patient in need thereof a therapeuticallyor prophylactically effective amount of a solid form comprisingpomalidomide and a coformer as described herein. Examples of activeagents include, but are not limited to, the second active agentsdescribed herein (see paragraph [00190] supra).

Examples of adverse effects associated with active agents used to treatMPD include, but are not limited to: conversion to acute leukemia;severe myelosuppression; gastrointestinal toxicity such as, but notlimited to, early and late-forming diarrhea and flatulence;gastrointestinal bleeding; nausea; vomiting; anorexia; leukopenia;anemia; neutropenia; asthenia; abdominal cramping; fever, pain; loss ofbody weight; dehydration; alopecia; dyspnea; insomnia; dizziness;mucositis; xerostomia; mucocutaneous lesions; and kidney failure.

In one embodiment, provided herein is a method of treating, preventing,or managing MPD, comprising administering to a patient (e.g., a human) asolid form comprising pomalidomide and a coformer as described herein,before, during, or after transplantation therapy.

In one embodiment, provided herein are pharmaceutical compositions,single unit dosage forms, and kits, comprising a solid form comprisingpomalidomide and a coformer as described herein, a second activeingredient, and/or blood or cells for transplantation therapy. Forexample, a kit may comprise a solid form comprising pomalidomide and acoformer as described herein, stem cells for transplantation, animmunosuppressive agent, and an antibiotic or other drug.

In one embodiment, provided herein is a method of modulating thedifferentiation of CD34⁺ stem, precursor, or progenitor cells to apredominantly erythroid lineage, comprising administering to a patientan effective amount of a solid form comprising pomalidomide and acoformer as described herein.

In one embodiment, provided herein is a method of modulatingdifferentiation of a CD34⁺ cell to an erythroid lineage comprisingdifferentiating said cell under suitable conditions and in the presenceof pomalidomide.

The CD34⁺ cell may be any stem, progenitor, or committed cell able todifferentiate into an erythroid cell. Such cells may be totipotent orpluripotent, or may be committed to a hematopoietic lineage. The CD34⁺cell may be derived from any source; in particular embodiments,“embryonic-like” stem cells derived from the placenta. For a descriptionof such embryonic-like stem cells and methods of obtaining them, seeU.S. application publication no. US 2003/0180269 A1, published Sep. 25,2003, which is incorporated by reference herein in its entirety. OtherCD34⁺ cells useful for the methods provided herein include stem cellsobtained from any tissue (such as, for example, hematopoietic stem cellsor embryonic stem cells) and non-committed progenitor cells from anytissue. Such CD34⁺ cells may be heterologous or autologous withreference to the intended recipient, when such cells, thedifferentiation of which is modulated according to the methods providedherein, are used to treat anemia or a hemoglobinopathy.

Differentiation of the CD34⁺ cells may typically take place over thecourse of 3-6 days. In in vitro assays in which CD34⁺ cells are culturedin the presence of pomalidomide, changes in gene expression indicatingdifferentiation along an erythroid pathway may be evident by the thirdday of culture. In one embodiment, erythroid-specific gene expression issignificantly increased, and phenotypic characteristics of erythroidcells are present in the CD34⁺ cells by day 6 of culture.

In one embodiment, therefore, CD34⁺ cells may be cultured in vitro inthe presence of pomalidomide, for a period of days sufficient forerythroid-specific gene expression, particularly fetal hemoglobin geneexpression, and/or cell characteristics to appear. In variousembodiments, the CD34⁺ cells may be cultured for 3, 6, 9, or 12 days, ormore. A solid form comprising pomalidomide and a coformer or a solutionthereof may be introduced once at the start of culture, and culturingcontinued until differentiation is substantially complete, or for 3, 6,9, 12 or more days. Alternatively, a solid form comprising pomalidomideand a coformer or a solution thereof may be administered to a culture ofCD34⁺ cells a plurality of times during culture. The CD34⁺ cells may becultured and differentiated in the presence pomalidomide.

In one embodiment, a solid form comprising pomalidomide and a coformermay be used as a solution at any concentration from 0.01 μM to 10 mM. Incertain embodiments, the concentration is between 0.01 μM and 10 μM.

In addition to differentiating CD34⁺ cells in vitro, such cells may bedifferentiated within an individual, in vivo. In one embodiment, such anindividual is a mammal, for example a human. As with in vitrodifferentiation of CD34⁺ cells, CD34⁺ cells within an individual may bedifferentiated by administration of a solid form comprising pomalidomideand a coformer as described herein. Such administration may be in theform of a single dose. Alternatively, the individual may be administereda solid form comprising pomalidomide and a coformer as described hereina plurality of times. Such administration may be performed, for example,over a period of 3, 6, 9, 12, or more days.

Where differentiation of CD34⁺ cells is to be accomplished in vivo,differentiation may be accomplished using pomalidomide alone, or acombination with a second active agent. For example, for an individualhaving a hemoglobinopathy such as sickle cell anemia or a thalassemia,who has a higher than normal level of SCF and/or erythropoietin, in vivodifferentiation may be accomplished by administration of a solid formcomprising pomalidomide and a coformer as described herein. Conversely,where an individual suffers an anemia that is the result of, or ischaracterized by, a lower-than-normal level of erythropoietic cytokines(e.g., SCF or erythropoietin), such cytokines may be administered alongwith, or prior to, administration of a solid form comprisingpomalidomide and a coformer. For example, an individual suffering fromchemotherapy-induced anemia may be administered one or more cytokines(e.g., a combination of SCF, Flt-3L, and/or IL-3) for, e.g., 3-6 days,followed by administration for, e.g., 3-6 days, of the solid formcomprising pomalidomide and a coformer, particularly with SCF anderythropoietin, in an amount sufficient to cause a detectable increasein fetal hemoglobin expression in CD34⁺ cells of said individual.Alternatively, CD34⁺ cells may be contacted with one or more cytokinesin vitro (e.g., SCF, Flt-3L, and/or IL-3) for, e.g., 3-6 days, followedby administration of the cells to an individual, along with SCF anderythropoictin in an amount sufficient to cause a detectable increase infetal hemoglobin expression in the CD34⁺ cells. Such administration maybe performed a single time or multiple times, and any one or more ofsuch administrations may be accompanied by the administration of a solidform comprising pomalidomide and a coformer, a second active agent, or acombination thereof.

In one embodiment is provided a method of inducing one or more genesassociated with or essential for erythropoiesis or hematopoiesis,comprising contacting an hematopoietic stem, progenitor or precursorcell with pomalidomide in the presence of erythropoietin and stem cellfactor, wherein said pomalidomide is present in a sufficient amount tocause said hematopoietic stem, progenitor or precursor cell to expressone or more genes encoding fetal hemoglobin. In a specific embodiment,said hematopoietic stem, progenitor or precursor cell is a CD34⁺ cell.In another specific embodiment, said one or more genes associated withor essential for erythropoiesis or hematopoiesis are genes encodingKruppel-like factor 1 erythroid; rhesus blood group-associatedglycoprotein; glycophorin B; integrin alpha 2b; erythroid-associatedfactor; glycophorin A; Kell blood group precursor; hemoglobin α2; solutecarrier 4, anion exchanger; carbonic anhydrase hemoglobin γA; hemoglobinγG; hemoglobin ϵ1; or any combination of the foregoing.

In some embodiments, the CD34⁺ cells are additionally differentiated,either in vivo or in vitro, in the presence of one or more cytokines.Cytokines useful to direct CD34⁺ cells along an erythroiddifferentiation pathway include, but are not limited to, erythropoietin(Epo), TNFα, stem cell factor (SCF), Flt-3L, and granulocytemacrophage-colony stimulating factor (GM-CSF). Epo and SCF are known tobe erythropoietic cytokines. Thus, in one embodiment, CD34⁺ cells aredifferentiated in the presence of Epo or SCF. In another embodiment, theCD34⁺ cells are differentiated in the presence of Epo and SCF. Inanother embodiment, the CD34⁺ cells are differentiated in the presenceof a combination of TNFα, SCF, Flt-3L, and/or GM-CSF. In anotherembodiment, said cells that are differentiated are one or more cells incell culture. In another embodiment, said cells that are differentiatedare cells within an individual. In an embodiment of in vitrodifferentiation, one or more of Epo, TNFα, SCF, Flt-3L and GM-CSF iscontacted with pomalidomide. In an embodiment of in vivodifferentiation, one or more of Epo, TNFα, SCF, Flt-3L and GM-CSF isadministered to an individual in the same treatment regimen a the solidform comprising pomalidomide and a coformer as provided herein.

The cytokines used in the methods provided herein may benaturally-occurring cytokines, or may be an artificial derivative oranalog of the cytokines. For example, analogs or derivatives oferythropoietin that may be used in combination with a solid form orcompound provided herein include, but are not limited to, Aranesp™ andDarbopoietin™.

Cytokines used may be purified from natural sources or recombinantlyproduced. Examples of recombinant cytokines that may be used in themethods provided herein include filgrastim, or recombinantgranulocyte-colony stimulating factor (G-CSF), which is sold in theUnited States under the trade name Neupogen® (Amgen, Thousand Oaks,Calif.); sargramostim, or recombinant GM-CSF, which is sold in theUnited States under the trade name Leukine® (Immunex, Seattle, Wash.);recombinant Epo, which is sold in the United States under the trade nameEpogen® (Amgen, Thousand Oaks, Calif.); and methionyl stem cell factor(SCF), which is sold in the United States under the trade nameAncestim™. Recombinant and mutated forms of GM-CSF can be prepared asdescribed in U.S. Pat. Nos. 5,391,485; 5,393,870; and 5,229,496; all ofwhich are incorporated herein by reference. Recombinant and mutatedforms of G-CSF can be prepared as described in U.S. Pat. Nos. 4,810,643;4,999,291; 5,528,823; and 5,580,755; all of which are incorporatedherein by reference.

Other cytokines may be used which encourage the survival and/orproliferation of hematopoietic precursor cells and immunologicallyactive poietic cells in vitro or in vivo, or which stimulate thedivision and differentiation of committed erythroid progenitors in cellsin vitro or in vivo. Such cytokines include, but are not limited to:interleukins, such as IL-2 (including recombinant IL-II (“rIL2”) andcanarypox IL-2), IL-10, IL-12, and IL-18; interferons, such asinterferon alfa-2a, interferon alfa-2b, interferon alfa-n1, interferonalfa-n3, interferon beta-I a, and interferon gamma-I b; and G-CSF.

When administered to a person having a hemoglobinopathy, a solid formcomprising pomalidomide and a coformer as described herein, particularlyin the presence of Epo, particularly in the presence of the combinationof TNFα, SCF, Flt-3L and GM-CSF, or more particularly in the presence ofEpo and SCF, induces the production of erythrocytes, and the productionof fetal hemoglobin as well as the production of AHSP. As noted above,cytokines used may include purified or recombinant forms, or analogs orderivatives of specific cytokines.

A solid form comprising pomalidomide and a coformer as described hereinmay also be administered in conjunction with one or more secondcompounds known to have, or suspected of having, a beneficial effect ona hemoglobinopathy. In this context, “beneficial effect” means anyreduction of any symptom of a hemoglobinopathy or anemia.

For example, with specific reference to the hemoglobinopathy sickle cellanemia, the second compound can be a compound, other than a pomalidomideor a derivative thereof, that is known or suspected to induce theproduction of fetal hemoglobin. Such compounds include hydroxyurea, andbutyrates or butyrate derivatives. The second compound may also be acompound that relaxes blood vessels, such as nitrous oxide, e.g.,exogenously-applied or administered nitrous oxide. The second compoundmay also be a compound that binds directly to hemoglobin S, preventingit from assuming the sickle-inducing conformation. For example, theplant extract known as HEMOXIN™ (NIPRISAN™; see U.S. Pat. No.5,800,819), which is an extract of a mixture of about 12 to about 17parts by weight of Piper guineense seeds, from about 15 to about 19parts by weight of Pterocarpus osun stem, from about 12 to about 18parts by weight of Eugenia caryophyllata fruit, and from about 25 toabout 32 parts by weight of Sorghum bicolor leaves, and optionally 15-22parts by weight potash, wherein the mixture is extracted with coldwater, has antisickling activity. The second compound may also be aGardos channel antagonist. Examples of Gardos channel antagonistsinclude clotrimazole and triaryl methane derivatives. The secondcompound may also be one that reduces red blood cell adhesion, therebyreducing the amount of clotting pervasive in sickle cell anemia.

Other hemoglobinopathies may be treated with a second compound known orsuspected to be efficacious for the specific condition. For example, βthalassemia may additionally be treated with the second compoundDeferoxamine, an iron chelator that helps prevent the buildup of iron inthe blood, or folate (vitamin B9). Thalassemia or sickle cell anemia mayalso be treated with protein C as the second compound (U.S. Pat. No.6,372,213). There is some evidence that herbal remedies can amelioratesymptoms of hemoglobinopathies, e.g., thalassemia; such remedies, andany of the specific active compounds contained therein, may also be usedas a second compound in the method provided herein. See, e.g., Wu Zhikuiet al. “The Effect of Bushen Shengxue Fang on β-thalassemia at the GeneLevel,” Journal of Traditional Chinese Medicine 18(4): 300-303 (1998);U.S. Pat. No. 6,538,023 “Therapeutic Uses of Green Tea Polyphenols forSickle Cell Disease”. Treatment of autoimmune hemolytic anemia caninclude corticosteroids as the second compound.

Second compounds that are proteins may also be derivatives or analogs ofother proteins. Such derivatives may include, but are not limited to,proteins that lack carbohydrate moieties normally present in theirnaturally occurring forms (e.g., nonglycosylated forms), pegylatedderivatives, and fusion proteins, such as proteins formed by fusing IgG1or IgG3 to the protein or active portion of the protein of interest.See, e.g., Penichet, M. L. and Morrison, S. L., J. Immunol. Methods248:91-101 (2001).

Cytokines and/or other compounds potentially useful in the treatment ofanemia or a hemoglobinopathy may be administered at the same time aspomalidomide or a derivative thereof. In this regard, the cytokines orother compounds may be administered as formulations separate from asolid form comprising pomalidomide and a coformer, or, where possible,may be compounded with a solid form comprising pomalidomide and acoformer for administration as a single pharmaceutical composition.Alternatively, the cytokines, the other compounds, or both, may beadministered separately from a solid form comprising pomalidomide and acoformer used in the methods provided herein, and may follow the same ordifferent dosing schedules. In one embodiment, a solid form comprisingpomalidomide and a coformer, cytokines, and/or any other compound usefulto treat anemia or a hemoglobinopathy, are administered at the sametime, but in separate pharmaceutical formulations for flexibility inadministration.

In addition to the treatment combinations outlined herein, the treatedindividual may be given transfusions. Such transfusions may be of blood,for example matched blood, or of a blood substitute such as Hemospan™ orHemospan™ PS (Sangart).

In any of the treatment combinations described herein, the treatedindividual is eukaryotic. In one embodiment, the treated individual is amammal, for example a human.

The methods described herein may be used to treat any anemia, includinganemia resulting from a hemoglobinopathy. Hemoglobinopathies and anemiastreatable by the methods provided herein may be genetic in origin, suchas sickle-cell anemia or thalassemias. The hemoglobinopathy may be dueto a disease, such as cancer, including, but not limited to, cancers ofthe hematopoietic or lymphatic systems. Other conditions treatable usingthe methods provided herein include hypersplenism, splenectomy, bowelresection, and bone marrow infiltration. The methods described hereinmay also be used to treat anemia resulting from the deliberate oraccidental introduction of a poison, toxin, or drug. For example,anemias resulting from cancer chemotherapies may be treated using themethods and solid forms provided herein. As such, the methods describedherein may be employed when anemia or a hemoglobinopathy is the primarycondition to be treated, or is a secondary condition caused by anunderlying disease or treatment regimen.

In one embodiment, the diseases or disorders are various forms ofleukemias such as chronic lymphocytic leukemia, chronic myelocyticleukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, andacute myeloblastic leukemia, including leukemias that are relapsed,refractory, or resistant, as disclosed in U.S. publication no.2006/0030594, published Feb. 9, 2006, which is incorporated in itsentirety by reference.

The term “leukemia” refers malignant neoplasms of the blood-formingtissues. The leukemia includes, but is not limited to, chroniclymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblasticleukemia, acute myelogenous leukemia, and acute myeloblastic leukemia.The leukemia can be relapsed, refractory or resistant to conventionaltherapy. The term “relapsed” refers to a situation where patients whohave had a remission of leukemia after therapy have a return of leukemiacells in the marrow and a decrease in normal blood cells. The term“refractory or resistant” refers to a circumstance where patients, evenafter intensive treatment, have residual leukemia cells in their marrow.

In another embodiment, the diseases or disorders are various types oflymphomas, including Non-Hodgkin's lymphoma (NHL). The term “lymphoma”refers a heterogenous group of neoplasms arising in thereticuloendothelial and lymphatic systems. “NHL” refers to malignantmonoclonal proliferation of lymphoid cells in sites of the immunesystem, including lymph nodes, bone marrow, spleen, liver, andgastrointestinal tract. Examples of NHL include, but are not limited to,mantle cell lymphoma (MCL), lymphocytic lymphoma of intermediatedifferentiation, intermediate lymphocytic lymphoma (ILL), diffuse poorlydifferentiated lymphocytic lymphoma (PDL), centrocytic lymphoma, diffusesmall-cleaved cell lymphoma (DSCCL), follicular lymphoma, and any typeof the mantle cell lymphomas that can be seen under the microscope(nodular, diffuse, blastic and mentle zone lymphoma).

Examples of diseases and disorders associated with, or characterized by,undesired angiogenesis include, but are not limited to, inflammatorydiseases, autoimmune diseases, viral diseases, genetic diseases,allergic diseases, bacterial diseases, ocular neovascular diseases,choroidal neovascular diseases, retina neovascular diseases, andrubeosis (neovascularization of the angle). Specific examples of thediseases and disorders associated with, or characterized by, undesiredangiogenesis include, but are not limited to, arthritis, endometriosis,Crohn's disease, heart failure, advanced heart failure, renalimpairment, endotoxemia, toxic shock syndrome, osteoarthritis,retrovirus replication, wasting, meningitis, silica-induced fibrosis,asbestos-induced fibrosis, veterinary disorder, malignancy-associatedhypercalcemia, stroke, circulatory shock, periodontitis, gingivitis,macrocytic anemia, refractory anemia, and 5q-deletion syndrome.

Other disease or disorders treated, prevented, or managed include, butnot limited to, viral, genetic, allergic, and autoimmune diseases.Specific examples include, but are not limited to, HIV, hepatitis, adultrespiratory distress syndrome, bone resorption diseases, chronicpulmonary inflammatory diseases, dermatitis, cystic fibrosis, septicshock, sepsis, endotoxic shock, hemodynamic shock, sepsis syndrome, postischemic reperfusion injury, meningitis, psoriasis, fibrotic disease,cachexia, graft versus host disease, graft rejection, auto-immunedisease, rheumatoid spondylitis, Crohn's disease, ulcerative colitis,inflammatory-bowel disease, multiple sclerosis, systemic lupuserythrematosus, ENL in leprosy, radiation damage, cancer, asthma, orhyperoxic alveolar injury.

In certain embodiments, a solid form provided herein, or a compositioncomprising a solid form provided herein, is administered orally,parenterally, topically, or mucosally. Examples of such dosage forms canbe found in section 5.5, infra.

In certain embodiments, a solid form provided herein, or a compositioncomprising a solid form provided herein, is administered at a dosingfrequency of once, twice, thrice, or four times daily. In certainembodiments, solid form provided herein, or a composition comprising asolid form provided herein, comprises pomalidomide in an amount of fromabout 0.1 to about 100 mg, from about 0.5 to about 50 mg, from, about0.5 to about 25 mg, from about 1 mg to about 10 mg, from about 0.5 toabout 5 mg, or from about 1 mg to about 5 mg. In certain embodiments,provided herein is a single unit dosage form suitable for oraladministration to a human comprising: an amount equal to or greater thanabout 1, 2, 3, 4, or 5 mg of a solid form comprising pomalidomide and acoformer provided herein; and a pharmaceutically acceptable excipient.In one embodiment, the amount of the active ingredient is about 0.5 mg.In another embodiment, the amount of the active ingredient is about 1mg. In another embodiment, the amount of the active ingredient is about2 mg. In another embodiment, the amount of the active ingredient isabout 4 mg.

In one embodiment, the second active agent is administered intravenouslyor subcutaneously and once or twice daily, once every other day, onceevery week, once every two weeks, or once every three weeks, in anamount of from about 1 to about 1000 mg, from about 5 to about 500 mg,from about 10 to about 350 mg, or from about 50 to about 200 mg. In oneembodiment, the second active agent is administered orally and once ortwice daily, once every other day, once every week, once every twoweeks, or once every three weeks, in an amount of from about 1 to about1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg,from about 10 to about 200 mg, from about 10 to about 100 mg, or fromabout 20 to about 50 mg. In specific embodiments, the second activeagent is administered once every week in an amount of about 40 mg. Thespecific amount of the second active agent will depend on the specificagent used, the type of disease being treated or managed, the severityand stage of disease, and the amount(s) of compounds provided herein andany optional additional active agents concurrently administered to thepatient.

As discussed elsewhere herein, also encompassed is a method of reducing,treating and/or preventing adverse or undesired effects associated withconventional therapy including, but not limited to, surgery,chemotherapy, radiation therapy, hormonal therapy, biological therapyand immunotherapy. Compounds provided herein and other activeingredients can be administered to a patient prior to, during, or afterthe occurrence of the adverse effect associated with conventionaltherapy.

5.4 Cycling Therapy

In certain embodiments, the prophylactic or therapeutic agents providedherein are cyclically administered to a patient. Cycling therapyinvolves the administration of an active agent for a period of time,followed by a rest (i.e., discontinuation of the administration) for aperiod of time, and repeating this sequential administration. Cyclingtherapy can reduce the development of resistance to one or more of thetherapies, avoid or reduce the side effects of one of the therapies,and/or improve the efficacy of the treatment.

Consequently, in one embodiment, a compound provided herein isadministered daily in a single or divided doses in a four to six weekcycle with a rest period of about a week or two weeks. Cycling therapyfurther allows the frequency, number, and length of dosing cycles to beincreased. Thus, another embodiment encompasses the administration of acompound provided herein for more cycles than are typical when it isadministered alone. In yet another embodiment, a compound providedherein is administered for a greater number of cycles than wouldtypically cause dose-limiting toxicity in a patient to whom a secondactive ingredient is not also being administered.

In one embodiment, a compound provided herein is administered daily andcontinuously for three or four weeks at a dose of from about 0.1 mg toabout 5 mg per day, followed by a rest of one or two weeks. In otherembodiments, the dose can be from about 1 mg to about 5 mg per day(e.g., 1, 2, 3, or 4 mg/day), given on Days 1-21 of each 28-day cycleuntil disease progression, followed by a rest of 7 days on Days 22-28 ofeach 28-day cycle, for example, in patients with relapsed and refractorymultiple myeloma who are refractory to their last myeloma therapy andhave received at least 2 prior therapies that included lenalidomide andbortezomib.

In one embodiment, a compound provided herein and a second activeingredient are administered orally, with administration of the compoundprovided herein occurring 30 to 60 minutes prior to the second activeingredient, during a cycle of four to six weeks. In another embodiment,the combination of a compound provided herein and a second activeingredient is administered by intravenous infusion over about 90 minutesevery cycle.

In one embodiment, a compound provided herein is administered at a doseof about 4 mg per day given on Days 1-21, followed by a rest of 7 dayson Days 22-28 of each 28-day cycle, alone or in combination with lowdose dexamethasone (e.g., 40 mg/day given on Days 1, 8, 15 and 22 ofeach 28-day cycle), for example, in patients with relapsed andrefractory multiple myeloma who are refractory to their last myelomatherapy and have received at least 2 prior therapies that includedlenalidomide and bortezomib.

5.5 Pharmaceutical Compositions and Dosage Forms

Pharmaceutical compositions can be used in the preparation of singleunit dosage forms comprising one or more solid forms provided herein. Inone embodiment, provided herein are pharmaceutical compositions anddosage forms comprising one or more solid forms comprising a compoundprovided herein, or a pharmaceutically acceptable salt, solvate (e.g.,hydrate), stereoisomer, co-crystal, clathrate, or prodrug thereof.Pharmaceutical compositions and dosage forms provided herein can furthercomprise one or more pharmaceutically acceptable excipients or carriers.

In some embodiments, pharmaceutical compositions and dosage formsprovided herein can also comprise one or more additional activeingredients. Examples of optional second, or additional, activeingredients are disclosed herein elsewhere.

In one embodiment, single unit dosage forms provided herein are suitablefor oral, parenteral (e.g., subcutaneous, intravenous, bolus injection,intramuscular, or intraarterial), topical (e.g., eye drops or otherophthalmic preparations), mucosal (e.g., nasal, sublingual, vaginal,buccal, or rectal), or transdermal administration to a patient. Examplesof dosage forms include, but are not limited to: tablets; caplets;capsules, such as soft elastic gelatin capsules or hard gelatincapsules; cachets; troches; lozenges; dispersions; suppositories;powders; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosageforms suitable for oral or mucosal administration to a patient,including suspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; eye drops or other ophthalmic preparations suitable fortopical administration; and sterile solids (e.g., crystalline oramorphous solids) that can be reconstituted to provide liquid dosageforms suitable for parenteral administration to a patient. In oneembodiment, the single dosage forms provided herein are tablets,caplets, or capsules comprising one or more solid forms provided herein.In one embodiment, the single dosage forms provided herein are tabletsor capsules comprising one or more solid forms provided herein.

The composition, shape, and type of dosage forms will typically varydepending on their use. For example, a dosage form used in the acutetreatment of a disease may contain larger amounts of one or more of theactive ingredients it comprises than a dosage form used in the chronictreatment of the same disease. Similarly, a parenteral dosage form maycontain smaller amounts of one or more of the active ingredients itcomprises than an oral dosage form used to treat the same disease. Theseand other ways in which specific dosage forms are used will vary fromone another will be readily apparent to those skilled in the art. See,e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing,Easton Pa. (1990).

In one embodiment, pharmaceutical compositions and dosage forms compriseone or more excipients or carriers. Suitable excipients are known tothose skilled in the art of pharmacy, and non-limiting examples ofsuitable excipients are provided herein. Whether a particular excipientis suitable for incorporation into a pharmaceutical composition ordosage form depends on a variety of factors known in the art including,but not limited to, the way in which the dosage form will beadministered to a patient. For example, oral dosage forms such astablets may contain excipients not suited for use in parenteral dosageforms. The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients may be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines are particularly susceptibleto such accelerated decomposition. Consequently, in one embodiment,provided are pharmaceutical compositions and dosage forms that containlittle, if any, lactose or other mono- or di-saccharides. As usedherein, the term “lactose-free” means that the amount of lactosepresent, if any, is insufficient to substantially increase thedegradation rate of an active ingredient. Lactose-free compositionsprovided herein can comprise excipients which are known in the art andare listed in the U.S. Pharmacopeia (USP) 25-NF20 (2002), which isincorporated herein in its entirety.

Also provided are anhydrous pharmaceutical compositions and dosage formscomprising active ingredient(s), since water may facilitate thedegradation of some compounds. Anhydrous pharmaceutical compositions anddosage forms can be prepared using anhydrous or low moisture containingingredients and low moisture or low humidity conditions. An anhydrouspharmaceutical composition should be prepared and stored such that itsanhydrous nature is maintained. Accordingly, in one embodiment,anhydrous compositions are packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

Also provided are pharmaceutical compositions and dosage forms thatcomprise one or more compounds that reduce the rate by which an activeingredient will decompose. Such compounds, which are referred to hereinas “stabilizers,” include, but are not limited to, antioxidants such asascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. In one embodiment, dosage forms comprise the activeingredient or solid from comprising pomalidomide and a coformer providedherein in an amount of from about 0.10 to about 10 mg, or from about0.10 to about 5 mg. In other embodiments, dosage forms comprise acompound provided herein in an amount of about 0.1, 0.2, 0.3, 0.4, 0.5,0.6, 0.7, 0.8, 0.9, 1, 2, 2.5, 3, 4, or 5 mg.

In other embodiments, dosage forms comprise a second active ingredientin an amount from about 1 mg to about 1000 mg, from about 5 mg to about500 mg, from about 10 mg to about 350 mg, from about 5 mg to about 250mg, from about 5 mg to about 100 mg, from about 10 mg to about 100 mg,from about 10 mg to about 50 mg, or from about 50 mg to about 200 mg. Inone embodiment, the specific amount of the second active agent willdepend on the specific agent used, the diseases or disorders beingtreated or managed, and the amount(s) of a compound provided herein, andany optional additional active agents concurrently administered to thepatient.

In particular embodiments, provided herein is a pharmaceuticalcomposition comprising a solid form comprising pomalidomide and acoformer provided herein and a pharmaceutically acceptable excipient orcarrier. In particular embodiments, provided herein is a pharmaceuticalcomposition comprising a cocrystal comprising pomalidomide and acoformer provided herein and a pharmaceutically acceptable excipient orcarrier. In particular embodiments, provided herein is a pharmaceuticalcomposition comprising an amorphous pomalidomide provided herein and apharmaceutically acceptable excipient or carrier. Exemplary embodimentsof formulations of pomalidomide are described in, for example, U.S. Pat.Nos. 5,635,517, 6,335,349, 6,316,471, 6,476,052, 7,041,680, and7,709,502; and U.S. Patent Application Publication No. 2011/0045064; theentireties of which are incorporated herein by reference.

5.5.1 Oral Dosage Forms

Pharmaceutical compositions that are suitable for oral administrationcan be provided as discrete dosage forms, such as, but not limited to,tablets, fastmelts, chewable tablets, capsules, pills, strips, troches,lozenges, pastilles, cachets, pellets, medicated chewing gum, bulkpowders, effervescent or non-effervescent powders or granules, oralmists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs,and syrups. In one embodiment, such dosage forms contain predeterminedamounts of active ingredients, and may be prepared by methods ofpharmacy known to those skilled in the art. See generally, Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).As used herein, oral administration also includes buccal, lingual, andsublingual administration.

In one embodiment, the oral dosage form provided herein is a tablet. Inone embodiment, the oral dosage form provided herein is a capsule. Inone embodiment, the oral dosage form provided herein is a caplet. Inparticular embodiments,

In one embodiment, oral dosage forms provided herein are prepared bycombining the active ingredients in an intimate admixture with one ormore pharmaceutically acceptable carrier or excipient, including, butnot limited to, binders, fillers, diluents, disintegrants, wettingagents, lubricants, glidants, coloring agents, dye-migration inhibitors,sweetening agents, flavoring agents, emulsifying agents, suspending anddispersing agents, preservatives, solvents, non-aqueous liquids, organicacids, and sources of carbon dioxide, according to conventionalpharmaceutical compounding techniques. Excipients can take a widevariety of forms depending on the form of preparation desired foradministration. For example, excipients suitable for use in oral liquidor aerosol dosage forms include, but are not limited to, water, glycols,oils, alcohols, flavoring agents, preservatives, and coloring agents.Examples of excipients suitable for use in solid oral dosage forms(e.g., powders, tablets, capsules, and caplets) include, but are notlimited to, starches, sugars, micro-crystalline cellulose, diluents,granulating agents, lubricants, binders, and disintegrating agents.

In one embodiment, oral dosage forms are tablets or capsules, in whichcase solid excipients are employed. In specific embodiments, capsulescomprising one or more solid forms comprising pomalidomide and acoformer provided herein can be used for oral administration. In oneembodiment, the total amount of pomalidomide in the capsule is about 1mg, about 2 mg, about 3 mg, about 4 mg, or about 5 mg. In oneembodiment, the total amount of pomalidomide in the capsule is about 1mg, about 2 mg, or about 4 mg. In one embodiment, the total amount ofpomalidomide in the capsule is about 1 mg or about 2 mg. Each capsulecan contain pomalidomide as the active ingredient and one or more of thefollowing inactive ingredients: mannitol, pregelatinized starch andsodium stearyl fumarate. In specific embodiments, the 1 mg capsule shellcan contain gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide,white ink and black ink. In specific embodiments, the 2 mg capsule shellcan contain gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide,FD&C red 3 and white ink. In another embodiment, tablets can be coatedby standard aqueous or nonaqueous techniques. Such dosage forms can beprepared by any of the methods of pharmacy. In general, pharmaceuticalcompositions and dosage forms are prepared by uniformly and intimatelyadmixing the active ingredients with liquid carriers, finely dividedsolid carriers, or both, and then shaping the product into the desiredpresentation if necessary.

In certain embodiments, the dosage form is a tablet, wherein the tabletis manufactured using standard, art-recognized tablet processingprocedures and equipment. In certain embodiments, the method for formingthe tablets is direct compression of a powdered, crystalline and/orgranular composition comprising a solid form provided herein, alone orin combination with one or more excipients, such as, for example,carriers, additives, polymers, or the like. In certain embodiments, asan alternative to direct compression, the tablets may be prepared usingwet granulation or dry granulation processes. In certain embodiments,the tablets are molded rather than compressed, starting with a moist orotherwise tractable material. In certain embodiments, compression andgranulation techniques are used.

In certain embodiments, the dosage form is a capsule, wherein thecapsules may be manufactured using standard, art-recognized capsuleprocessing procedures and equipments. In certain embodiments, softgelatin capsules may be prepared in which the capsules contain a mixturecomprising a solid form provided herein and vegetable oil ornon-aqueous, water miscible materials, such as, for example,polyethylene glycol and the like. In certain embodiments, hard gelatincapsules may be prepared containing granules of solid forms providedherein in combination with a solid pulverulent carrier, such as, forexample, lactose, saccharose, sorbitol, mannitol, potato starch, cornstarch, amylopectin, cellulose derivatives, or gelatin. In certainembodiments, a hard gelatin capsule shell may be prepared from a capsulecomposition comprising gelatin and a small amount of plasticizer such asglycerol. In certain embodiments, as an alternative to gelatin, thecapsule shell may be made of a carbohydrate material. In certainembodiments, the capsule composition may additionally include polymers,colorings, flavorings and opacifiers as required. In certainembodiments, the capsule comprises HPMC.

Examples of excipients or carriers that can be used in oral dosage formsprovided herein include, but are not limited to, diluents (bulkingagents), lubricants, disintegrants, fillers, stabilizers, surfactants,preservatives, coloring agents, flavoring agents, binding agents(binders), excipient supports, glidants, permeation enhancementexcipients, plasticizers and the like, e.g., as known in the art. Itwill be understood by those in the art that some substances serve morethan one purpose in a pharmaceutical composition. For instance, somesubstances are binders that help hold a tablet together aftercompression, yet are also disintegrants that help break the tablet apartonce it reaches the target delivery site. Selection of excipients andamounts to use may be readily determined by the formulation scientistbased upon experience and consideration of standard procedures andreference works available in the art.

In certain embodiments, dosage forms provided herein comprise one ormore binders. Binders may be used, e.g., to impart cohesive qualities toa tablet or a capsule, and thus ensure that the formulation remainsintact after compression. Suitable binders include, but are not limitedto, starch (including potato starch, corn starch, and pregelatinizedstarch), gelatin, sugars (including sucrose, glucose, dextrose andlactose), polyethylene glycol, propylene glycol, waxes, and natural andsynthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone(PVP), cellulosic polymers (including hydroxypropyl cellulose (HPC),hydroxypropylmethylcellulose (HPMC), methyl cellulose, ethyl cellulose,hydroxyethyl cellulose (HEC), carboxymethyl cellulose and the like),veegum, carbomer (e.g., carbopol), sodium, dextrin, guar gum,hydrogenated vegetable oil, magnesium aluminum silicate, maltodextrin,polymethacrylates, povidone (e.g., KOLLIDON, PLASDONE), microcrystallinecellulose, among others. Binding agents also include, e.g., acacia,agar, alginic acid, cabomers, carrageenan, cellulose acetate phthalate,ceratonia, chitosan, confectioner's sugar, copovidone, dextrates,dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum,hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylcellulose, hydroxypropyl starch, hypromellose, inulin, lactose,magnesium aluminum silicate, maltodextrin, maltose, methylcellulose,poloxamer, polycarbophil, polydextrose, polyethylene oxide,polymethylacrylates, povidone, sodium alginate, sodiumcarboxymethylcellulose, starch, pregelatinized starch, stearic acid,sucrose, and zein. In one embodiment, the binding agent can be, relativeto the weight of the dosage form, in an amount of from about 50% toabout 99% w/w. In certain embodiments, a suitable amount of a particularbinder is determined by one of ordinary skill in the art.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (FMC Corporation, Marcus Hook, Pa.), and mixturesthereof. In one embodiment, a specific binder is a mixture ofmicrocrystalline cellulose and sodium carboxymethyl cellulose sold asAVICEL RC-581. Suitable anhydrous or low moisture excipients oradditives include AVICEL-PH-103™ and Starch 1500 LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms provided herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in a pharmaceutical composition is, in oneembodiment, present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

In certain embodiments, dosage forms provided herein comprise one ormore diluents. Diluents may be used, e.g., to increase bulk so that apractical size tablet or capsule is ultimately provided. Suitablediluents include dicalcium phosphate, calcium sulfate, lactose,cellulose, kaolin, mannitol, sodium chloride, dry starch,microcrystalline cellulose (e.g., AVICEL), microfine cellulose,pregelitinized starch, calcium carbonate, calcium sulfate, sugar,dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate,tribasic calcium phosphate, kaolin, magnesium carbonate, magnesiumoxide, maltodextrin, mannitol, polymethacrylates (e.g., EUDRAGIT),potassium chloride, sodium chloride, sorbitol and talc, among others.Diluents also include, e.g., ammonium alginate, calcium carbonate,calcium phosphate, calcium sulfate, cellulose acetate, compressiblesugar, confectioner's sugar, dextrates, dextrin, dextrose, erythritol,ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate,isomalt, kaolin, lacitol, lactose, mannitol, magnesium carbonate,magnesium oxide, maltodextrin, maltose, medium-chain triglycerides,microcrystalline cellulose, microcrystalline silicified cellulose,powered cellulose, polydextrose, polymethylacrylates, simethicone,sodium alginate, sodium chloride, sorbitol, starch, pregelatinizedstarch, sucrose, sulfobutylether-β-cyclodextrin, talc, tragacanth,trehalose, and xylitol. Diluents may be used in amounts calculated toobtain a desired volumn for a tablet or capsule. The amount of a diluentin the pharmaceutical compositions provided herein varies upon the typeof formulation, and is readily discernible to those of ordinary skill inthe art.

Disintegrants may be used in the compositions to provide tablets orcapsules that disintegrate when exposed to an aqueous environment.Dosage forms that contain too much disintegrant may disintegrate instorage, while those that contain too little may not disintegrate at adesired rate or under the desired conditions. Thus, a sufficient amountof disintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredient(s) may be used to form solidoral dosage forms. The amount of disintegrant used varies based upon thetype of formulation, and is readily discernible to those of ordinaryskill in the art. In one embodiment, pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant, orfrom about 1 to about 5 weight percent of disintegrant.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of a disintegrant in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The amount of a disintegrant in the pharmaceutical compositionsprovided herein varies upon the type of formulation, and is readilydiscernible to those of ordinary skill in the art.

Lubricants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, calcium stearate, magnesiumstearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.Additional lubricants include, for example, a syloid silica gel(AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), acoagulated aerosol of synthetic silica (marketed by Degussa Co. ofPlano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. The pharmaceuticalcompositions provided herein may contain about 0.1 to about 5% by weightof a lubricant.

Suitable glidants include, but are not limited to, colloidal silicondioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and asbestos-freetalc. Suitable coloring agents include, but are not limited to, any ofthe approved, certified, water soluble FD&C dyes, and water insolubleFD&C dyes suspended on alumina hydrate, and color lakes and mixturesthereof. A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Suitable flavoring agents include, but arenot limited to, natural flavors extracted from plants, such as fruits,and synthetic blends of compounds which produce a pleasant tastesensation, such as peppermint and methyl salicylate. Suitable sweeteningagents include, but are not limited to, sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include, but are not limited to,gelatin, acacia, tragacanth, bentonite, and surfactants, such aspolyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylenesorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitablesuspending and dispersing agents include, but are not limited to, sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodiumcarbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrrolidone. Suitable preservatives include, but are notlimited to, glycerin, methyl and propylparaben, benzoic add, sodiumbenzoate and alcohol. Suitable wetting agents include, but are notlimited to, propylene glycol monostearate, sorbitan monooleate,diethylene glycol monolaurate, and polyoxyethylene lauryl ether.Suitable solvents include, but are not limited to, glycerin, sorbitol,ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized inemulsions include, but are not limited to, mineral oil and cottonseedoil. Suitable organic acids include, but are not limited to, citric andtartaric acid. Suitable sources of carbon dioxide include, but are notlimited to, sodium bicarbonate and sodium carbonate.

In one embodiment, a solid oral dosage form comprises a compoundprovided herein, and one or more excipients selector from anhydrouslactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid,colloidal anhydrous silica, and gelatin. In one embodiment, capsulescomprise one or more solid forms comprising pomalidomide and a coformerprovided herein, and one or more of the following inactive ingredients:mannitol, pregelatinized starch, sodium stearyl fumarate, gelatin,titanium dioxide, FD&C blue 2, yellow iron oxide, white ink, black ink,FD&C red 3, and a combination thereof.

The pharmaceutical compositions provided herein for oral administrationcan be provided as compressed tablets, tablet triturates, chewablelozenges, rapidly dissolving tablets, multiple compressed tablets, orenteric-coating tablets, sugar-coated, or film-coated tablets.Enteric-coated tablets are compressed tablets coated with substancesthat resist the action of stomach acid but dissolve or disintegrate inthe intestine, thus protecting the active ingredients from the acidicenvironment of the stomach. Enteric-coatings include, but are notlimited to, fatty acids, fats, phenyl salicylate, waxes, shellac,ammoniated shellac, and cellulose acetate phthalates. Sugar-coatedtablets are compressed tablets surrounded by a sugar coating, which maybe beneficial in covering up objectionable tastes or odors and inprotecting the tablets from oxidation. Film-coated tablets arecompressed tablets that are covered with a thin layer or film of awater-soluble material. Film coatings include, but are not limited to,hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000, and cellulose acetate phthalate. Film coating imparts thesame general characteristics as sugar coating. Multiple compressedtablets are compressed tablets made by more than one compression cycle,including layered tablets, and press-coated or dry-coated tablets.

The tablet dosage forms can be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein for oral administrationcan be provided as soft or hard capsules, which can be made fromgelatin, methylcellulose, starch, or calcium alginate. The hard gelatincapsule, also known as the dry-filled capsule (DFC), consists of twosections, one slipping over the other, thus completely enclosing theactive ingredient. The soft elastic capsule (SEC) is a soft, globularshell, such as a gelatin shell, which is plasticized by the addition ofglycerin, sorbitol, or a similar polyol. The soft gelatin shells maycontain a preservative to prevent the growth of microorganisms. Suitablepreservatives are those as described herein, including methyl- andpropyl-parabens, and sorbic acid. The liquid, semisolid, and soliddosage forms provided herein may be encapsulated in a capsule. Suitableliquid and semisolid dosage forms include solutions and suspensions inpropylene carbonate, vegetable oils, or triglycerides. Capsulescontaining such solutions can be prepared as described in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient.

The pharmaceutical compositions provided herein for oral administrationcan be provided in liquid and semisolid dosage forms, includingemulsions, solutions, suspensions, elixirs, and syrups. An emulsion is atwo-phase system, in which one liquid is dispersed in the form of smallglobules throughout another liquid, which can be oil-in-water orwater-in-oil. Emulsions may include a pharmaceutically acceptablenon-aqueous liquid or solvent, emulsifying agent, and preservative.Suspensions may include a pharmaceutically acceptable suspending agentand preservative. Aqueous alcoholic solutions may include apharmaceutically acceptable acetal, such as a di(lower alkyl) acetal ofa lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and awater-miscible solvent having one or more hydroxyl groups, such aspropylene glycol and ethanol. Elixirs are clear, sweetened, andhydroalcoholic solutions. Syrups are concentrated aqueous solutions of asugar, for example, sucrose, and may also contain a preservative. For aliquid dosage form, for example, a solution in a polyethylene glycol maybe diluted with a sufficient quantity of a pharmaceutically acceptableliquid carrier, e.g., water, to be measured conveniently foradministration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations can further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administrationcan be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein for oral administrationcan be provided as non-effervescent or effervescent, granules andpowders, to be reconstituted into a liquid dosage form. Pharmaceuticallyacceptable carriers and excipients used in the non-effervescent granulesor powders may include diluents, sweeteners, and wetting agents.Pharmaceutically acceptable carriers and excipients used in theeffervescent granules or powders may include organic acids and a sourceof carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The pharmaceutical compositions provided herein for oral administrationcan be formulated as immediate or modified release dosage forms,including delayed-, sustained, pulsed-, controlled, targeted-, andprogrammed-release forms.

6. EXAMPLES

Certain embodiments provided herein are illustrated by the followingnon-limiting examples.

In one embodiment, pomalidomide may be synthesized using methodsdescribed in U.S. Pat. Nos. 5,635,517, 6,335,349, 6,316,471, 6,476,052,7,041,680, 7,709,502, and 7,994,327, all of which are incorporatedherein in their entireties.

6.1 Preparation of Cocrystal Comprising Pomalidomide and a Coformer

Method A (Stoichiometric Slurry Experiments): Stoichiometric slurryexperiments were carried out in glass vials. Each of the vials wascharged with about 20 mg of pomalidomide, an approximately equimolaramount of coformer, and 500 μL of a saturated solution of the samecoformer in the solvent used for that experiment. A magnetic stir barwas placed in each vial and the rack of vials was placed on a stir plateat room temperature for 24 hours. The solids were isolated bycentrifugation.

Method B (Stoichiometric Wet Milling Experiments): For each experiment,A PEEK grinding cup was charged with about 20 mg of pomalidomide, anapproximately equimolar amount of coformer, about 10 μL of a mixture ofmethanol and water (3:1), and one steel grinding ball. The cup wassealed and shaken on a Retsch mill for 20 min. The solid was collected.

Method C (Stoichiometric Flash Evaporation Experiments): The solvent wasremoved from solutions containing about 20 mg of pomalidomide andapproximately equimolar amount of coformer on a rotary evaporator usinga bath set at 65° C. If the residue was solid it was stored at 75%relative humidity for 1 day. If the residue was oil it was stored at 60°C. overnight. The resulting solids were collected.

In one exemplary study, a cocrystal comprising pomalidomide and gallicacid was prepared by method A as described above using a solvent ofDMF:acetone (1:2). In another embodiment, a cocrystal comprisingpomalidomide and gallic acid was prepared by method C as describedabove.

In one exemplary study, a cocrystal comprising pomalidomide and vanillinwas prepared by method B as described above. In another embodiment, acocrystal comprising pomalidomide and vanillin was prepared by method Cas described above.

In one exemplary study, a cocrystal comprising pomalidomide and cyclamicacid was prepared by method A as described above using a solvent ofDMF:acetone (1:2).

In one exemplary study, a cocrystal comprising pomalidomide andD-glucose was prepared by method A as described above using a solvent ofDMF:MeOH (1:1).

In one exemplary study, a cocrystal comprising pomalidomide and propylgallate was prepared by method A as described above using a solvent ofDMF:MeOH (1:1).

In one exemplary study, a cocrystal comprising pomalidomide andsaccharin was prepared by method A as described above using a solvent ofDMF:MeOH (1:1).

In one exemplary study, a cocrystal comprising pomalidomide and sodiumlauryl sulfate was prepared by method B as described above.

In one exemplary study, a cocrystal comprising pomalidomide andmagnesium bromide was prepared by method C as described above.

In one exemplary study, a cocrystal comprising pomalidomide and malonicacid was prepared by method C as described above.

In one exemplary study, a cocrystal comprising pomalidomide and maltolwas prepared by method C as described above.

In one exemplary study, a cocrystal comprising pomalidomide and methylparaben was prepared by method C as described above.

In one exemplary study, a cocrystal comprising pomalidomide and zincchloride was prepared by method C as described above.

In one exemplary study, a pure Form B of pomalidomide was prepared byrotary evaporation of a solution of pomalidomide in a 95:5 mixture oftetrahydrofuran and water.

All of the samples generated were analyzed by XRPD. The Rigaku Smart-LabX-ray diffraction system was configured for reflection Bragg-Brentanogeometry using a line source X-ray beam. The x-ray source was a Cu LongFine Focus tube that was operated at 40 kV and 44 ma. That sourceprovided an incident beam profile at the sample that changed from anarrow line at high angles to a broad rectangle at low angles. Beamconditioning slits were used on the line X-ray source to ensure that themaximum beam size was less than 10 mm both along the line and normal tothe line. The Bragg-Brentano geometry was a para-focusing geometrycontrolled by passive divergence and receiving slits with the sampleitself acting as the focusing component for the optics. The inherentresolution of Bragg-Brentano geometry was governed in part by thediffractometer radius and the width of the receiving slit used.Typically, the Rigaku Smart-Lab was operated to give peak widths of 0.1°2θ or less. The axial divergence of the X-ray beam was controlled by5.0-degree Soller slits in both the incident and diffracted beam paths.

Powder samples were prepared in a low background Si holder using lightmanual pressure to keep the sample surfaces flat and level with thereference surface of the sample holder. The single-crystal, Si,low-background holder had a small circular recess (7 mm diameter andabout 1 mm depth) that held between 5 and 10 mg of powdered material.Each sample was analyzed from 2 to 40° 2θ using a continuous scan of 3°2θ per minute with an effective step size of 0.02° 2θ.

DSC analyses were performed using a TA Instruments Q5000 DSC equippedwith an autosampler tray. The instrument was cooled using a TAInstrument Refrigerated Cooling System (RCS) 90 chiller. Each sample wasweighed into a Tzero DSC pan, covered with a Tzero lid, and crimped. Thesample pan was placed in the DSC autosampler tray for automated loadingand analysis. An empty crimped Tzero pan was used as a reference and wasalso placed in the autosampler tray for automated loading. Duringanalysis, the sample was heated from ambient temperature to about 350°C. at a rate of 10° C./minute. The instrument was controlled usingThermal Advantage Release 5.2.5 software and the data were analyzedusing Universal Analysis 2000 for Windows version 4.5A.

TGA analyses were performed using a TA Instruments Q50 TGA with externalheat exchanger. Each sample was loaded into a platinum TGA pan, whichwas then loaded onto the instrument. During analysis, the sample washeated from ambient temperature to about 350° C. at a rate of 10°C./minute. The instrument was controlled using Thermal Advantage Release5.2.5 software and the data were analyzed using Universal Analysis 2000for Windows version 4.5A.

The general characterization methods described herein are non-limiting,and are intended merely as examples of parameters, methods andtechniques which can be used to analyze certain embodiments providedherein. Other standard parameters, methods and techniques for chemical,biological, physiological and solid-state analysis are contemplatedherein as means of characterizing various embodiments provided herein.

Solubility of pomalidomide in various solvents at ambient temperaturewas determined and is shown in Table 1. Solubility was estimated bytreating a weighed sample of pomalidomide with measured aliquots of thetest solvent at ambient temperature, with shaking and/or sonicationbetween aliquots. Dissolution was determined by visual inspection.Solubility numbers were calculated by dividing the total amount ofsolvent used to dissolve the sample by the weight of the sample. Theactual solubilities may be greater than the numbers calculated becauseof the use of solvent aliquots that were too large or because of slowdissolution rates. The solubility number is expressed as “less than” ifdissolution did not occur during the experiment. The solubility numberis expressed as “greater than” if dissolution occurred on addition ofthe first solvent aliquot.

TABLE 1 Solubility of Pomalidomide Solvent Solubility (mg/mL) Acetone0.9 Acetonitrile <1 Dichloromethane <1 DMF >5 Hexafluoroisopropanol 2.3Methanol <1 2-methyltetrahydrofuran <1 tetrahydrofuran (THF) 1.12,2,2-trifluoroethanol <1 acetone:water (95:5) <1 DMF:acetone (1:2) 6.0DMF:methanol (1:1) 4.2 DMF:methanol (1:2) 2.4 THF:water (95:5) 3.5

6.2 Assays

6.2.1 TNFα Inhibition Assay in PBMC

Peripheral blood mononuclear cells (PBMC) from normal donors areobtained by Ficoll Hypaque (Pharmacia, Piscataway, N.J., USA) densitycentrifugation. Cells are cultured in RPMI 1640 (Life Technologies,Grand Island, N.Y., USA) supplemented with 10% AB+human serum (GeminiBio-products, Woodland, Calif., USA), 2 mM L-glutamine, 100 U/mlpenicillin, and 100 μg/ml streptomycin (Life Technologies).

PBMC (2×10⁵ cells) are plated in 96-well flat-bottom Costar tissueculture plates (Corning, N.Y., USA) in triplicate. Cells are stimulatedwith LPS (from Salmonella abortus equi, Sigma cat. no. L-1887, St.Louis, Mo., USA) at 1 ng/mL final in the absence or presence ofcompounds. Compounds provided herein are dissolved in DMSO (Sigma) andfurther dilutions are done in culture medium immediately before use. Thefinal DMSO concentration in all assays can be about 0.25%. Compounds areadded to cells 1 hour before LPS stimulation. Cells are then incubatedfor 18-20 hours at 37° C. in 5% CO₂, and supernatants are thencollected, diluted with culture medium and assayed for TNFα levels byELISA (Endogen, Boston, Mass., USA). IC₅₀s are calculated usingnon-linear regression, sigmoidal dose-response, constraining the top to100% and bottom to 0%, allowing variable slope (GraphPad Prism v3.02).

6.2.2 IL-2 and MIP-3α Production by T Cells

PBMC are depleted of adherent monocytes by placing 1×10⁸ PBMC in 10 mlcomplete medium (RPMI 1640 supplemented with 10% heat-inactivated fetalbovine serum, 2 mM L-glutamine, 100 U/ml penicillin, and 100 μg/mlstreptomycin) per 10 cm tissue culture dish, in 37° C., 5% CO₂ incubatorfor 30-60 minutes. The dish is rinsed with medium to remove allnon-adherent PBMC. T cells are purified by negative selection using thefollowing antibody (Pharmingen) and Dynabead (Dynal) mixture for every1×10⁸ non-adherent PBMC: 0.3 ml Sheep anti-mouse IgG beads, 15 μlanti-CD16, 15 μl anti-CD33, 15 μl anti-CD56, 0.23 ml anti-CD19 beads,0.23 ml anti-HLA class II beads, and 56 μl anti-CD14 beads. The cellsand bead/antibody mixture is rotated end-over-end for 30-60 minutes at4° C. Purified T cells are removed from beads using a Dynal magnet.Typical yield is about 50% T cells, 87-95% CD3⁺ by flow cytometry.

Tissue culture 96-well flat-bottom plates are coated with anti-CD3antibody OKT3 at 5 μg/ml in PBS, 100 μl per well, incubated at 37° C.for 3-6 hours, then washed four times with complete medium 100 μl/welljust before T cells are added. Compounds are diluted to 20 times offinal in a round bottom tissue culture 96-well plate. Finalconcentrations are about 10 μM to about 0.00064 μM. A 10 mM stock ofcompounds provided herein is diluted 1:50 in complete for the first 20×dilution of 200 μM in 2% DMSO and serially diluted 1:5 into 2% DMSO.Compound is added at 10 μl per 200 μl culture, to give a final DMSOconcentration of 0.1%. Cultures are incubated at 37° C., 5% CO₂ for 2-3days, and supernatants analyzed for IL-2 and MIP-3α by ELISA (R&DSystems). IL-2 and MIP-3α levels are normalized to the amount producedin the presence of an amount of a compound provided herein, and EC₅₀scalculated using non-linear regression, sigmoidal dose-response,constraining the top to 100% and bottom to 0%, allowing variable slope(GraphPad Prism v3.02).

6.2.3 Cell Proliferation Assay

Cell lines Namalwa, MUTZ-5, and UT-7 are obtained from the DeutscheSammlung von Mikroorganismen und Zellkulturen GmbH (Braunschweig,Germany). The cell line KG-1 is obtained from the American Type CultureCollection (Manassas, Va., USA). Cell proliferation as indicated by³H-thymidine incorporation is measured in all cell lines as follows.

Cells are plated in 96-well plates at 6000 cells per well in media. Thecells are pre-treated with compounds at about 100, 10, 1, 0.1, 0.01,0.001, 0.0001 and 0 μM in a final concentration of about 0.25% DMSO intriplicate at 37° C. in a humidified incubator at 5% CO₂ for 72 hours.One microcurie of ³H-thymidine (Amersham) is then added to each well,and cells are incubated again at 37° C. in a humidified incubator at 5%CO₂ for 6 hours. The cells are harvested onto UniFilter GF/C filterplates (Perkin Elmer) using a cell harvester (Tomtec), and the platesare allowed to dry overnight. Microscint 20 (Packard) (25 μl/well) isadded, and plates are analyzed in TopCount NXT (Packard). Each well iscounted for one minute. Percent inhibition of cell proliferation iscalculated by averaging all triplicates and normalizing to the DMSOcontrol (0% inhibition). Each compound is tested in each cell line inthree separate experiments. Final IC₅₀s are calculated using non-linearregression, sigmoidal dose-response, constraining the top to 100% andbottom to 0%, allowing variable slope. (GraphPad Prism v3.02).

6.2.4 Immunoprecipitation and Immunoblot

Namalwa cells are treated with DMSO or an amount of a compound providedherein for 1 hour, then stimulated with 10 U/ml of Epo (R&D Systems) for30 minutes. Cell lysates are prepared and either immunoprecipitated withEpo receptor Ab or separated immediately by SDS-PAGE. Immunoblots areprobed with Akt, phospo-Akt (Ser473 or Thr308), phospho-Gab1 (Y627),Gab1, IRS2, actin and IRF-1 Abs and analyzed on a Storm 860 Imager usingImageQuant software (Molecular Dynamics).

6.2.5 Cell Cycle Analysis

Cells are treated with DMSO or an amount of a compound provided hereinovernight. Propidium iodide staining for cell cycle is performed usingCycleTEST PLUS (Becton Dickinson) according to manufacturer's protocol.Following staining, cells are analyzed by a FACSCalibur flow cytometerusing ModFit LT software (Becton Dickinson).

6.2.6 Apoptosis Analysis

Cells are treated with DMSO or an amount of a compound provided hereinat various time points, then washed with annexin-V wash buffer (BDBiosciences). Cells are incubated with annexin-V binding protein andpropidium iodide (BD Biosciences) for 10 minutes. Samples are analyzedusing flow cytometry.

6.2.7 Luciferase Assay

Namalwa cells are transfected with 4 μg of AP1-luciferase (Stratagene)per 1×10⁶ cells and 3 μl Lipofectamine 2000 (Invitrogen) reagentaccording to manufacturer's instructions. Six hours post-transfection,cells are treated with DMSO or an amount of a compound provided herein.Luciferase activity is assayed using luciferase lysis buffer andsubstrate (Promega) and measured using a luminometer (Turner Designs).

The embodiments described above are intended to be merely exemplary, andthose skilled in the art will recognize, or will be able to ascertainusing no more than routine experimentation, numerous equivalents ofspecific compounds, materials, and procedures. All such equivalents areconsidered to be within the scope of the disclosure and are encompassedby the appended claims.

All of the patents, patent applications and publications referred toherein are incorporated herein in their entireties. Citation oridentification of any reference in this application is not an admissionthat such reference is available as prior art. The full scope of thedisclosure is better understood with reference to the appended claims.

What is claimed is:
 1. A method of treating multiple myeloma, the method comprising administering to a patient a solid form comprising (a) 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (pomalidomide); and (b) a coformer; wherein the coformer is gallic acid and the solid form has an X-ray powder diffraction (XRPD) pattern comprising peaks at 22.98, 26.16, and 26.90 degrees 2θ±0.2 degrees 2θ; the coformer is vanillin and the solid form has an XRPD pattern comprising peaks at 13.09, 17.30, and 25.61 degrees 2θ±0.2 degrees 2θ; the coformer is cyclamic acid and the solid form has an XRPD pattern comprising peaks at 6.42, 7.88, and 15.73 degrees 2θ±0.2 degrees 2θ; the coformer is D-glucose and the solid form has an XRPD pattern comprising peaks at 17.09, 20.68, and 25.52 degrees 2θ±0.2 degrees 2θ; the coformer is propyl gallate and the solid form has an XRPD pattern comprising peaks at 7.78, 25.23, and 25.61 degrees 2θ±0.2 degrees 2θ; the coformer is saccharin and the solid form has an XRPD pattern comprising peaks at 15.98, 19.09, and 25.10 degrees 2θ±0.2 degrees 2θ; the coformer is sodium lauryl sulfate and the solid form has an XRPD pattern comprising peaks at 2.66, 5.30, and 7.93 degrees 2θ±0.2 degrees 2θ; the coformer is magnesium bromide and the solid form has an XRPD pattern comprising peaks at 3.23, 28.76, and 29.95 degrees 2θ±0.2 degrees 2θ; the coformer is malonic acid and the solid form has an XRPD pattern comprising peaks at 12.23, 16.63, and 25.58 degrees 2θ±0.2 degrees 2θ; the coformer is maltol and the solid form has an XRPD pattern comprising peaks at 16.51, 17.09, and 25.73 degrees 2θ±0.2 degrees 2θ; the coformer is methyl paraben and the solid form has an XRPD pattern comprising peaks at 18.73, 25.69, and 26.70 degrees 2θ±0.2 degrees 2θ; or the coformer is zinc chloride and the solid form has an XRPD pattern comprising peaks at 2.38, 17.17, and 25.71 degrees 2θ±0.2 degrees 2θ.
 2. The method of claim 1, wherein the coformer is gallic acid and the solid form has an X-ray powder diffraction pattern comprising peaks at 22.98, 26.16, and 26.90 degrees 2θ±0.2 degrees 2θ.
 3. The method of claim 2, having an X-ray powder diffraction pattern further comprising peaks at 15.52, 18.42 and 23.20 degrees 2θ±0.2 degrees 2θ.
 4. The method of claim 2, having an X-ray powder diffraction pattern substantially similar to the XRPD pattern presented in FIG.
 1. 5. The method of claim 1, wherein the coformer is vanillin and the solid form has an X-ray powder diffraction pattern comprising peaks at 13.09, 17.30, and 25.61 degrees 2θ±0.2 degrees 2θ.
 6. The method of claim 5, having an X-ray powder diffraction pattern further comprising peaks at 12.25, 16.91, and 28.01 degrees 2θ±0.2 degrees 2θ.
 7. The method of claim 5, having an X-ray powder diffraction pattern substantially similar to the XRPD pattern presented in FIG.
 2. 8. The method of claim 1, wherein the coformer is cyclamic acid and the solid form has an X-ray powder diffraction pattern comprising peaks at 6.42, 7.88, and 15.73 degrees 2θ±0.2 degrees 2θ.
 9. The method of claim 8, having an X-ray powder diffraction pattern further comprising peaks at 18.54 and 19.25 degrees 2θ±0.2 degrees 2θ.
 10. The method of claim 8, having an X-ray powder diffraction pattern substantially similar to the XRPD pattern presented in FIG.
 3. 11. The method of claim 1, wherein the coformer is D-glucose and the solid form has an X-ray powder diffraction pattern comprising peaks at 17.09, 20.68, and 25.52 degrees 2θ±0.2 degrees 2θ.
 12. The method of claim 11, having an X-ray powder diffraction pattern further comprising peaks at 12.31, 14.08, and 17.35 degrees 2θ±0.2 degrees 2θ.
 13. The method of claim 11, having an X-ray powder diffraction pattern substantially similar to the XRPD pattern presented in FIG.
 4. 14. The method of claim 1, wherein the coformer is propyl gallate and the solid form has an X-ray powder diffraction pattern comprising peaks at 7.78, 25.23, and 25.61 degrees 2θ±0.2 degrees 2θ.
 15. The method of claim 14, having an X-ray powder diffraction pattern further comprising peaks at 17.35 and 24.29 degrees 2θ±0.2 degrees 2θ.
 16. The method of claim 14, having an X-ray powder diffraction pattern substantially similar to the XRPD pattern presented in FIG.
 5. 17. The method of claim 1, wherein the coformer is saccharin and the solid form has an X-ray powder diffraction pattern comprising peaks at 15.98, 19.09, and 25.10 degrees 2θ±0.2 degrees 2θ.
 18. The method of claim 17, having an X-ray powder diffraction pattern further comprising peaks at 20.07 and 25.73 degrees 2θ±0.2 degrees 2θ.
 19. The method of claim 17, having an X-ray powder diffraction pattern substantially similar to the XRPD pattern presented in FIG.
 6. 20. The method of claim 1, wherein the coformer is sodium lauryl sulfate and the solid form has an X-ray powder diffraction pattern comprising peaks at 2.66, 5.30, and 7.93 degrees 2θ±0.2 degrees 2θ.
 21. The method of claim 20, having an X-ray powder diffraction pattern further comprising a peak at 2.20 degrees 2θ±0.2 degrees 2θ.
 22. The method of claim 20, having an X-ray powder diffraction pattern substantially similar to the XRPD pattern presented in FIG.
 7. 23. The method of claim 1, wherein the coformer is magnesium bromide and the solid form has an X-ray powder diffraction pattern comprising peaks at 3.23, 28.76, and 29.95 degrees 2θ±0.2 degrees 2θ.
 24. The method of claim 23, having an X-ray powder diffraction pattern further comprising peaks at 25.72 and 29.87 degrees 2θ±0.2 degrees 2θ.
 25. The method of claim 23, having an X-ray powder diffraction pattern substantially similar to the XRPD pattern presented in FIG.
 8. 26. The method of claim 1, wherein the coformer is malonic acid and the solid form has an X-ray powder diffraction pattern comprising peaks at 12.23, 16.63, and 25.58 degrees 2θ±0.2 degrees 2θ.
 27. The method of claim 26, having an X-ray powder diffraction pattern further comprising peaks at 17.27 and 24.29 degrees 2θ±0.2 degrees 2θ.
 28. The method of claim 26, having an X-ray powder diffraction pattern substantially similar to the XRPD pattern presented in FIG.
 9. 29. The method of claim 1, wherein the coformer is maltol and the solid form has an X-ray powder diffraction pattern comprising peaks at 16.51, 17.09, and 25.73 degrees 2θ±0.2 degrees 2θ.
 30. The method of claim 29, having an X-ray powder diffraction pattern further comprising peaks at 13.93 and 24.25 degrees 2θ±0.2 degrees 2θ.
 31. The method of claim 29, having an X-ray powder diffraction pattern substantially similar to the XRPD pattern presented in FIG.
 10. 32. The method of claim 1, wherein the coformer is methyl paraben and the solid form has an X-ray powder diffraction pattern comprising peaks at 18.73, 25.69, and 26.70 degrees 2θ±0.2 degrees 2θ.
 33. The method of claim 32, having an X-ray powder diffraction pattern further comprising peaks at 13.90 and 21.98 degrees 2θ±0.2 degrees 2θ.
 34. The method of claim 32, having an X-ray powder diffraction pattern substantially similar to the XRPD pattern presented in FIG.
 11. 35. The method of claim 1, wherein the coformer is zinc chloride and the solid form has an X-ray powder diffraction pattern comprising peaks at 2.38, 17.17, and 25.71 degrees 2θ±0.2 degrees 2θ.
 36. The method of claim 35, having an X-ray powder diffraction pattern further comprising peaks at 3.22 and 16.61 degrees 2θ±0.2 degrees 2θ.
 37. The method of claim 35, having an X-ray powder diffraction pattern substantially similar to the XRPD pattern presented in FIG.
 12. 38. The method of claim 1, wherein the molar ratio of 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione to the conformer is about 1:1. 